Substituted quinazoline compounds and methods of use thereof

ABSTRACT

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , A, B, G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , n, x, y, X and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

BACKGROUND Technical Field

The present invention is generally directed to novel compounds andmethods for their preparation and use as therapeutic or prophylacticagents, for example for treatment of cancer.

Description of the Related Art

RAS represents a group of closely related monomeric globular proteins of189 amino acids (21 kDa molecular mass) which are associated with theplasma membrane and which bind either GDP or GTP. RAS acts as amolecular switch. When RAS contains bound GDP, it is in the resting oroff position and is “inactive”. In response to exposure of the cell tocertain growth promoting stimuli, RAS is induced to exchange its boundGDP for a GTP. With GTP bound, RAS is “switched on” and is able tointeract with and activate other proteins (its “downstream targets”).The RAS protein itself has a very low intrinsic ability to hydrolyze GTPback to GDP, thus turning itself into the off state. Switching RAS offrequires extrinsic proteins termed GTPase-activating proteins (GAPs)that interact with RAS and greatly accelerate the conversion of GTP toGDP. Any mutation in RAS which affects its ability to interact with GAPor to convert GTP back to GDP will result in a prolonged activation ofthe protein and consequently a prolonged signal to the cell telling itto continue to grow and divide. Because these signals result in cellgrowth and division, overactive RAS signaling may ultimately lead tocancer.

Structurally, RAS proteins contain a G domain which is responsible forthe enzymatic activity of RAS—the guanine nucleotide binding and thehydrolysis (GTPase reaction). It also contains a C-terminal extension,known as the CAAX box, which may be post-translationally modified and isresponsible for targeting the protein to the membrane. The G domain isapproximately 21-25 kDa in size and it contains a phosphate binding loop(P-loop). The P-loop represents the pocket where the nucleotides arebound in the protein, and this is the rigid part of the domain withconserved amino acid residues which are essential for nucleotide bindingand hydrolysis (Glycine 12, Threonine 26 and Lysine 16). The G domainalso contains the so called Switch I (residues 30-40) and Switch II(residues 60-76) regions, both of which are the dynamic parts of theprotein which are often represented as the “spring-loaded” mechanismbecause of their ability to switch between the resting and loaded state.The key interaction is the hydrogen bonds formed by Threonine-35 andglycine-60 with the γ-phosphate of GTP which maintain Switch 1 andSwitch 2 regions respectively in their active conformation. Afterhydrolysis of GTP and release of phosphate, these two relax into theinactive GDP conformation.

The most notable members of the RAS subfamily are HRAS, KRAS and NRAS,mainly for being implicated in many types of cancer. However, there aremany other members including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS;NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C;RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2;RERG; RERGL; RRAD; RRAS and RRAS2.

Mutations in any one of the three main isoforms of RAS (HRAS, NRAS, orKRAS) genes are among the most common events in human tumorigenesis.About 30% of all human tumors are found to carry some mutation in RASgenes. Remarkably, KRAS mutations are detected in 25-30% of tumors. Bycomparison, the rates of oncogenic mutation occurring in the NRAS andHRAS family members are much lower (8% and 3% respectively). The mostcommon KRAS mutations are found at residue G12 and G13 in the P-loop andat residue Q61.

G12C is a frequent mutation of KRAS gene (glycine-12 to cysteine). Thismutation had been found in about 13% of cancer occurrences, about 43% oflung cancer occurrences, and in almost 100% of MYH-associates polyposis(familial colon cancer syndrome). However targeting this gene with smallmolecules is a challenge.

Accordingly, while progress has been made in this field, there remains aneed in the art for improved compounds and methods for treatment ofcancer, for example by inhibition of KRAS, HRAS or NRAS. The presentinvention fulfills this need and provides further related advantages.

BRIEF SUMMARY

In brief, the present invention provides compounds, includingstereoisomers, pharmaceutically acceptable salts, tautomers and prodrugsthereof, which are capable of modulating G12C mutant KRAS, HRAS and/orNRAS proteins. In some instances, the compounds act as electrophileswhich are capable of forming a covalent bond with the cysteine residueat position 12 of a KRAS, HRAS or NRAS G12C mutant protein. Methods foruse of such compounds for treatment of various diseases or conditions,such as cancer, are also provided.

In one embodiment, compounds having the following structure (I) areprovided:

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein R¹, R^(2a), R^(2b), R^(2c), R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), R⁶, G¹, G², L¹, L², m¹, m², n, X and E are as definedherein. Pharmaceutical compositions comprising one or more compounds ofstructure (I) and a pharmaceutically acceptable carrier are alsoprovided in various other embodiments.

In a different embodiment is provided a compound having the followingstructure (II):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein R¹, R^(2a), R^(2b), R^(2c), A, L¹, L² and E are as definedherein. Pharmaceutical compositions comprising one or more compounds ofstructure (II) and a pharmaceutically acceptable carrier are alsoprovided in various other embodiments.

In other different embodiments, a compound of structure (III) isprovided:

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein R¹, R^(2a), R^(2b), R^(2c), R^(3a), R^(3b), R^(4a), R^(4b), A,B, G¹, G², L¹, L², x, y and E are as defined herein. Pharmaceuticalcompositions comprising one or more compounds of structure (II) and apharmaceutically acceptable carrier are also provided in various otherembodiments.

In other embodiments, the present invention provides a method fortreatment of cancer, the method comprising administering an effectiveamount of a pharmaceutical composition comprising any one or more of thecompounds of structure (I), (II) or (III) to a subject in need thereof.

Other provided methods include a method for regulating activity of aKRAS, HRAS or NRAS G12C mutant protein, the method comprising reactingthe KRAS, HRAS or NRAS G12C mutant protein with any one of the compoundsof structure (I), (II) or (III). In other embodiments, a method forinhibiting proliferation of a cell population, the method comprisingcontacting the cell population with any one of the compounds ofstructure (I) is also provided.

In other embodiments, the invention is directed to a method for treatinga disorder mediated by a KRAS, HRAS or NRAS G12C mutation in a subjectin need thereof, the method comprising:

determining if the subject has a KRAS, HRAS or NRAS G12C mutation; and

if the subject is determined to have the KRAS, HRAS or NRAS G12Cmutation, then administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising any one or morecompounds of structure (I), (II) or (III).

In still more embodiments, the invention is directed to a method forpreparing a labeled KRAS, HRAS or NRAS G12C mutant protein, the methodcomprising reacting the KRAS, HRAS or NRAS G12C mutant with a compoundof structure (I), (II) or (III), to result in the labeled KRAS, HRAS orNRAS G12C protein.

These and other aspects of the invention will be apparent upon referenceto the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements.The sizes and relative positions of elements in the figures are notnecessarily drawn to scale and some of these elements are arbitrarilyenlarged and positioned to improve figure legibility.

Further, the particular shapes of the elements as drawn are not intendedto convey any information regarding the actual shape of the particularelements, and have been solely selected for ease of recognition in thefigures.

FIG. 1 illustrates the enzymatic activity of RAS.

FIG. 2 depicts a signal transduction pathway for RAS.

FIG. 3 shows some common oncogenes, their respective tumor type andcumulative mutation frequencies (all tumors).

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details.

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. As used in the specification andclaims, the singular form “a”, “an” and “the” include plural referencesunless the context clearly dictates otherwise.

“Amidinyl” refers to a radical of the form —(C═NR_(a))NR_(b)R_(c),wherein R_(a), R_(b) and R_(c) are each independently H or C₁-C₆ alkyl.

“Amino” refers to the —NH₂ radical.

“Aminylsulfone” refers to the —S(O)₂NH₂ radical.

“Carboxy” or “carboxyl” refers to the —CO₂H radical.

“Cyano” refers to the —CN radical.

“Guanidinyl” refers to a radical of the form—NR_(d)(C═NR_(a))NR_(b)R_(c), wherein R_(a), R_(b), R_(c), and R_(d) areeach independently H or C₁-C₆ alkyl.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Alkyl includes alkenyls (one or more carbon-carbon double bonds)and alkynyls (one or more carbon-carbon triple bonds such as ethynyl andthe like). “Amidinylalkyl” refers to an alkyl group comprising at leastone amidinyl substituent. “Guanidinylalkyl” refers to an alkyl groupcomprising at least one guanidinyl substituent. Unless stated otherwisespecifically in the specification, an alkyl, amidinylalkyl and/orguanidinylalkyl group is optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain is optionally substituted.

“Alkylcycloalkyl” refers to a radical of the formula —R_(b)R_(a) whereR_(b) is cycloalkyl as defined herein and R_(d) is an alkyl radical asdefined above. Unless stated otherwise specifically in thespecification, a alkylcycloalkyl group is optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.“Amidinylalkyloxy” refers to an alkoxy group comprising at least oneamidinyl substituent on the alkyl group. “Guanidinylalkyloxy” refers toan alkoxy group comprising at least one guanidinyl substituent on thealkyl group. “Alkylcarbonylaminylalkyloxy” refers to an alkoxy groupcomprising at least one alkylcarbonylaminyl substituent on the alkylgroup. “Heterocyclylalkyloxy” refers to an alkoxy group comprising atleast one heterocyclyl substituent on the alkyl group.“Heteroarylalkyloxy” refers to an alkoxy group comprising at least oneheteroaryl substituent on the alkyl group. “Aminylalkyloxy” refers to analkoxy group comprising at least one substituent of the form—NR_(a)R_(b), where R_(a) and R_(b) are each independently H or C₁-C₆alkyl, on the alkyl group. Unless stated otherwise specifically in thespecification, an alkoxy, amidinylalkyloxy, guanidinylalkyloxy,alkylcarbonylaminyl, heterocyclylalkyloxy, heteroarlyalkyloxy and/oraminylalkyloxy group is optionally substituted.

“Alkoxyalkyl” refers to a radical of the formula —R_(b)OR_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms and R_(b) is an alkylene radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkoxyalkyl group is optionallysubstituted.

“Alkoxycarbonyl” refers to a radical of the formula —C(═O)OR_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms. Unless stated otherwise specifically in the specification,an alkoxycarbonyl group is optionally substituted.

“Aryloxy” refers to a radical of the formula —OR_(a) where R_(a) is anaryl radical as defined herein. Unless stated otherwise specifically inthe specification, an aryloxy group is optionally substituted.

“Alkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical asdefined above containing one to twelve carbon atoms. A “haloalkylaminyl”group is an alkylaminyl group comprising at least one halo substituenton the alkyl group. A “hydroxylalkylaminyl” group is an alkylaminylgroup comprising at least one hydroxyl substituent on the alkyl group.An “amidinylalkylaminyl” group is an alkylaminyl group comprising atleast one amidinyl substituent on the alkyl group. A“guanidinylalkylaminyl” group is an alkylaminyl group comprising atleast one guanidinyl substituent on the alkyl group. Unless statedotherwise specifically in the specification, an alkylaminyl,haloalkylaminyl, hydroxylalkylaminyl, amidinylalkylaminyl and/orguanidinylalkylaminyl group is optionally substituted.

“Aminylalkyl” refers to an alkyl group comprising at least one aminylsubstituent (—NR_(a)R_(b) wherein R_(a) and R_(b) are each independentlyH or C₁-C₆ alkyl). The aminyl substituent can be on a tertiary,secondary or primary carbon. In some embodiments od aminylalkyl, bothR_(a) and R_(b) are H. Unless stated otherwise specifically in thespecification, an aminylalkyl group is optionally substituted.

“Aminylalkylaminyl” refers to a radical of the formula —NR_(a)R_(b)wherein R_(a) is H or C₁-C₆ alkyl and R_(b) is aminylalkyl. Unlessstated otherwise specifically in the specification, an aminylalkylaminylgroup is optionally substituted.

“Aminylalkoxy” refers to a radical of the formula —OR_(a)NH₂ whereinR_(a) is alkylene. Unless stated otherwise specifically in thespecification, an aminylalkoxy group is optionally substituted.

“Alkylaminylalkoxy” refers to a radical of the formula—OR_(a)NR_(b)R_(c) wherein R_(a) is alkylene and R_(b) and R_(c) areeach independently H or C₁-C₆ alkyl, provided one of R_(b) or R_(c) isC₁-C₆ alkyl. Unless stated otherwise specifically in the specification,an alkylaminylalkoxy group is optionally substituted.

“Alkylcarbonylaminyl” refers to a radical of the formula —NH(C═O)R_(a)where R_(a) is an alkyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkylcarbonylaminyl group is optionally substituted.An alkenylcarbonylaminyl is an alkylcarbonylaminyl containing at leastone carbon-carbon double bond. An alkenylcarbonylaminyl group isoptionally substituted.

“Alkylcarbonylaminylalkoxy” refers to a radical of the formula—OR_(b)NH(C═O)R_(a) where R_(a) is an alkyl radical as defined abovecontaining one to twelve carbon atoms and R_(b) is alkylene. Unlessstated otherwise specifically in the specification, analkylcarbonylaminylalkoxy group is optionally substituted.

“Alkylaminylalkyl” refers to an alkyl group comprising at least onealkylaminyl substituent. The alkylaminyl substituent can be on atertiary, secondary or primary carbon. Unless stated otherwisespecifically in the specification, an alkylaminylalkyl group isoptionally substituted.

“Aminylcarbonyl” refers to a radical of the formula —C(═O)R_(a)R_(b)where R_(a) and R_(b) are each independently H or alkyl. Unless statedotherwise specifically in the specification, an aminylcarbonyl group isoptionally substituted.

“Alkylaminylcarbonyl” refers to a radical of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H oralkyl, provided at least one of R_(a) or R_(b) is alkyl. Unless statedotherwise specifically in the specification, an alkylaminylcarbonylgroup is optionally substituted.

“Aminylcarbonylalkyl” refers to a radical of the formula—R_(c)C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently Hor alkyl and R, is alkylene. Unless stated otherwise specifically in thespecification, an aminylcarbonylalkyl group is optionally substituted.

“Aminylcarbonycycloalkylalkyl” refers to a radical of the formula—R_(c)C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently Hor alkyl and R_(c) is cycloalkyl. Unless stated otherwise specificallyin the specification, an aminylcarbonylcycloalkyl group is optionallysubstituted.

“Aryl” refers to a carbocyclic ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical is a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsthat are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(e) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group is optionally substituted.

“Arylalkyloxy” refers to a radical of the formula —OR_(b)—R_(e) whereR_(b) is an alkylene chain as defined above and R_(c) is one or morearyl radicals as defined above, for example, benzyl, diphenylmethyl andthe like. Unless stated otherwise specifically in the specification, anarylalkyloxy group is optionally substituted.

“Arylalkylaminyl” refers to a radical of the formula—N(R_(a))R_(b)—R_(c) where R_(a) is H or C₁-C₆ alkyl, R_(b) is analkylene chain as defined above and R_(c) is one or more aryl radicalsas defined above, for example, benzyl, diphenylmethyl and the like.Unless stated otherwise specifically in the specification, anarylalkylaminyl group is optionally substituted.

“Carboxyalkyl” refers to a radical of the formula —R_(b)—R_(e) whereR_(b) is an alkylene chain as defined above and R_(c) is a carboxylgroup as defined above. Unless stated otherwise specifically in thespecification, carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a radical of the formula —R_(b)—R_(e) where R_(b)is an alkylene chain as defined above and R_(c) is a cyano group asdefined above. Unless stated otherwise specifically in thespecification, a cyanoalkyl group is optionally substituted.

“Carbocyclic” or “carbocycle” refers to a ring system, wherein each ofthe ring atoms are carbon.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycycliccarbocyclic radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.A “cycloalkenyl” is a cycloalkyl comprising one or more carbon-carbondouble bonds within the ring. Unless otherwise stated specifically inthe specification, a cycloalkyl (or cycloalkenyl) group is optionallysubstituted.

“Cyanocycloalkyl” refers to a radical of the formula —R_(b)—R_(c) whereR_(b) is cycloalkyl and R_(c) is a cyano group as defined above. Unlessstated otherwise specifically in the specification, a cyanocycloalkylgroup is optionally substituted.

“Cycloalkylaminylcarbonyl” refers to a radical of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H orcycloalkyl, provided at least one of R_(a) or R_(b) is cycloalkyl.Unless stated otherwise specifically in the specification, ncycloalkylaminylcarbonyl group is optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined above and R_(d) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group is optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring is replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group is optionally substituted.

“Haloalkoxy” refers to a radical of the formula —OR_(a) where R_(a) is ahaloalkyl radical as defined herein containing one to twelve carbonatoms. Unless stated otherwise specifically in the specification, ahaloalkoxy group is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical havingone to twelve ring carbonatoms (e.g., two to twelve) and from one to six ring heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur.Unless stated otherwise specifically in the specification, theheterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclicring system, which may include fused, spirocyclic (“spiro-heterocyclyl”)and/or bridged ring systems; and the nitrogen, carbon or sulfur atoms inthe heterocyclyl radical is optionally oxidized; the nitrogen atom isoptionally quatemized; and the heterocyclyl radical is partially orfully saturated.

Examples of such heterocyclyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification. “Heterocyclyloxy” refers to a heterocyclyl group bound tothe remainder of the molecule via an oxygen bond (—O—).“Heterocyclylaminyl” refers to a heterocyclyl group bound to theremainder of the molecule via a nitrogen bond (—NR_(a)—, where R_(a) isH or C₁-C₆ alkyl). Unless stated otherwise specifically in thespecification, a heterocyclyl, heterocyclyloxy and/or heterocyclylaminylgroup is optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group is optionallysubstituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(c) whereR_(b) is an alkylene chain as defined above and R_(c) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heterocyclylalkyl groupis optionally substituted.

“Heterocyclylalkyloxy” refers to a radical of the formula —OR_(b)R_(c)where R_(b) is an alkylene chain as defined above and R_(e) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heterocyclylalkyloxygroup is optionally substituted.

“Heterocyclylalkylaminyl” refers to a radical of the formula—N(R_(c))R_(b)R_(c) where R_(b) is an alkylene chain as defined aboveand R_(e) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl isoptionally attached to the alkyl radical at the nitrogen atom, R_(c) isH or C₁-C₆ alkyl. Unless stated otherwise specifically in thespecification, a heterocyclylalkyloxy group is optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen ring carbon atoms, one to sixring heteroatoms selected from the group consisting of nitrogen, oxygenand sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). “Heteroaryloxy” refers to aheteroaryl group bound to the remainder of the molecule via an oxygenbond (—O—). “Heteroarylaminyl” refers to a heteroaryl group bound to theremainder of the molecule via a nitrogen bond (—NR_(a)—, where R_(a) isH or C₁-C₆ alkyl). Unless stated otherwise specifically in thespecification, a heteroaryl, heteroaryloxy and/or heteroarylaminyl groupis optionally substituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group is optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined above and R_(f) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group is optionally substituted.

“Heteroarylalkyloxy” refers to a radical of the formula —OR_(b)R_(f)where R_(b) is an alkylene chain as defined above and R_(f) is aheteroaryl radical as defined above, and if the heteroaryl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heteroarylalkyloxy groupis optionally substituted.

“Heteroarylalkylaminyl” refers to a radical of the formula—NR_(c)R_(b)R_(f) where R_(b) is an alkylene chain as defined above andR_(f) is a heteroaryl radical as defined above, and if the heteroaryl isa nitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom, and R_(c) is H orC₁-C₆ alkyl. Unless stated otherwise specifically in the specification,a heteroarylalkyloxy group is optionally substituted. “Hydroxylalkyl”refers to an alkyl group comprising at least one hydroxyl substituent.The —OH substituent may be on a primary, secondary or tertiary carbon.Unless stated otherwise specifically in the specification, ahydroxylalkyl group is optionally substituted. “Hydroxylalkylaminyl” isan alkylaminyl groups comprising at least one —OH substituent, which ison a primary, secondary or tertiary carbon. Unless stated otherwisespecifically in the specification, a hydroxylalkylaminyl group isoptionally substituted.

“Phosphate” refers to the —OP(═O)(R_(a))R_(b) group, where R_(a) is OH,O⁻ or OR_(c) and R_(b) is OH, O⁻, O_(Rc), or a further phosphate group(e.g., to form a di- or triphosphate), wherein R_(c) is a counter ion(e.g., Na+ and the like).

“Phosphoalkoxy” refers to an alkoxy group, as defined herein, which issubstituted with at least least one phosphate group, as defined herein.Unless stated otherwise specifically in the specification, anphosphoalkoxy group is optionally substituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup is optionally substituted.

The term “substituted” used herein means any of the above groups (e.g.,alkyl, alkylene, alkylcycloalkyl, alkoxy, amidinylalkyloxy,guanidinylalkyloxy, alkylcarbonylaminylalkyloxy, heterocyclylalkyloxy,heteroarylalkyloxy, aminylalkyloxy, alkoxyalkyl, alkoxycarbonyl,haloalkylaminyl, hydroxylalkylaminyl, amidinylalkylaminyl,guanidinylalkylaminyl, aminylalkyl, aminylalkylaminyl, aminylalkoxy,alkylaminylalkoxy aryloxy, alkylaminyl, alkylcarbonylaminyl,alkylaminylalkyl, aminylcarbonyl, alkylaminylcarbonyl,alkylcarbonylaminylalkoxy, aminylcarbonylalkyl,aminylcarbonycycloalkylalkyl, thioalkyl, aryl, aralkyl, arylalkyloxy,arylalkylaminyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkyloxy,cycloalkylaminyl, cyanocycloalkyl, cycloalkylaminylcarbonyl,cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl, heterocyclyloxy,heterocyclylaminyl, N-heterocyclyl, heterocyclylalkyl,heterocyclylalkyloxy, heterocyclylalkylaminyl, heteroaryl, N-heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl,hydroxylalkylaminyl, phosphoalkoxy and/or hydroxylalkyl) wherein atleast one hydrogen atom (e.g., 1, 2, 3 or all hydrogen atoms) isreplaced by a bond to a non-hydrogen atom such as, but not limited to: ahalogen atom such as F, Cl, Br, and I; an oxygen atom in groups such ashydroxyl groups, alkoxy groups, and ester groups; a sulfur atom ingroups such as thiol groups, thioalkyl groups, sulfone groups, sulfonylgroups, and sulfoxide groups; a nitrogen atom in groups such as amines,amides, alkylamines, dialkylamines, arylamines, alkylarylamines,diarylamines, N-oxides, imides, and enamines; a silicon atom in groupssuch as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilylgroups, and triarylsilyl groups; and other heteroatoms in various othergroups. “Substituted” also means any of the above groups in which one ormore hydrogen atoms are replaced by a higher-order bond (e.g., a double-or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,carboxyl, and ester groups; and nitrogen in groups such as imines,oximes, hydrazones, and nitriles. For example, “substituted” includesany of the above groups in which one or more hydrogen atoms are replacedwith —NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)N R_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO₂NR_(g)R_(h). “Substituted also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. “Substituted” further means any of the above groups inwhich one or more hydrogen atoms are replaced by a bond to an aminyl,cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl group. In addition, each of theforegoing substituents may also be optionally substituted with one ormore of the above substituents.

“Electrophile” or “electrophilic moiety” is any moiety capable ofreacting with a nucleophile (e.g., a moiety having a lone pair ofelectrons, a negative charge, a partial negative charge and/or an excessof electrons, for example a —SH group). Electrophiles typically areelectron poor or comprise atoms which are electron poor. In certainembodiments an electrophile contains a positive charge or partialpositive charge, has a resonance structure which contains a positivecharge or partial positive charge or is a moiety in which delocalizationor polarization of electrons results in one or more atom which containsa positive charge or partial positive charge. In some embodiments, theelectrophiles comprise conjugated double bonds, for example anα,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment” or “treating” refer to an approach forobtaining beneficial or desired results with respect to a disease,disorder or medical condition including but not limited to a therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder. In certain embodiments, for prophylacticbenefit, the compositions are administered to a subject at risk ofdeveloping a particular disease, or to a subject reporting one or moreof the physiological symptoms of a disease, even though a diagnosis ofthis disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

All compounds of the invention (i.e., compounds of structure (I), (II)or (III)) which exist in free base or acid form can be converted totheir pharmaceutically acceptable salts by treatment with theappropriate inorganic or organic base or acid by methods known to oneskilled in the art. Salts of the compounds of the invention can beconverted to their free base or acid form by standard techniques.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the protein, such as KRAS, HRAS or NRAS G12C. Accordingly,the terms “antagonist” and “inhibitors” are defined in the context ofthe biological role of the target protein. While preferred antagonistsherein specifically interact with (e.g. bind to) the target, compoundsthat inhibit a biological activity of the target protein by interactingwith other members of the signal transduction pathway of which thetarget protein is a member are also specifically included within thisdefinition. A preferred biological activity inhibited by an antagonistis associated with the development, growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include a simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” refers to abiologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or indirect interaction withthe target.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Radiation therapy” means exposing a subject, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of structure (I), (II) or(III)). Thus, the term “prodrug” refers to a precursor of a biologicallyactive compound that is pharmaceutically acceptable. In some aspects, aprodrug is inactive when administered to a subject, but is converted invivo to an active compound, for example, by hydrolysis. The prodrugcompound often offers advantages of solubility, tissue compatibility ordelayed release in a mammalian organism (see, e.g., Bundgard, H., Designof Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussionof prodrugs is provided in Higuchi, T., et al., “Pro-drugs as NovelDelivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein. The term “prodrug” is alsomeant to include any covalently bonded carriers, which release theactive compound in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of an active compound, as described herein, aretypically prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

In some embodiments, prodrugs include compounds of structure (I), (II)or (III) having a phosphate, phosphoalkoxy, ester or boronic estersubstituent. Without being bound by theory, it is believed that suchsubstituents are converted to a hydroxyl group under physiologicalconditions. Accordingly, embodiments include any of the compoundsdisclosed herein, wherein a hydroxyl group has been replaced with aphosphate, phosphoalkoxy, ester or boronic ester group, for example aphosphate or phosphoalkoxy group. For example, in some embodiments ahydroxyl group on the R¹ moiety is replaced with a phosphate,phosphoalkoxy, ester or boronic ester group, for example a phosphate oralkoxy phosphate group. Exemplary prodrugs of certain embodiments thusinclude compounds having one of the following R¹ moieties:

wherein each R′ is independently H or an optional substituent, and n is1, 2, 3 or 4. The term “in vivo” refers to an event that takes place ina subject's body.

Embodiments of the invention disclosed herein are also meant toencompass all pharmaceutically acceptable compounds of structure (I),(II) or (III) being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds could be useful to helpdetermine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labeled compounds of structure (I), (II) or (III), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence are preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I), (II) or (III) can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the Preparations and Examplesas set out below using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Certain embodiments are also meant to encompass the in vivo metabolicproducts of the disclosed compounds. Such products may result from, forexample, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, embodiments include compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabeled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. In some embodiments, the solvent iswater, in which case the solvate is a hydrate. Alternatively, in otherembodiments, the solvent is an organic solvent. Thus, the compounds ofthe present invention may exist as a hydrate, including a monohydrate,dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and thelike, as well as the corresponding solvated forms. In some aspects, thecompound of the invention is a true solvate, while in other cases, thecompound of the invention merely retains adventitious water or is amixture of water plus some adventitious solvent.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

The compounds of the invention (i.e., compounds of structure (I), (II)or (III)), or their pharmaceutically acceptable salts may contain one ormore asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that are defined, in termsof absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-foramino acids. Embodiments thus include all such possible isomers, as wellas their racemic and optically pure forms. Optically active (+) and (−),(R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centres of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

Embodiments of the present invention include all manner of rotamers andconformationally restricted states of a compound of the invention.Atropisomers, which are stereoisomers arising because of hinderedrotation about a single bond, where energy differences due to stericstrain or other contributors create a barrier to rotation that is highenough to allow for isolation of individual conformers, are alsoincluded. As an example, certain compounds of the invention may exist asmixtures of atropisomers or purified or enriched for the presence of oneatropisomer. Non-limiting examples of compounds which exist asatropisomers include the following compounds:

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. Embodiments thus include tautomers ofthe disclosed compounds.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program and/or ChemDraw Ultra Version 11.0.1software naming program (CambridgeSoft). For complex chemical namesemployed herein, a substituent group is typically named before the groupto which it attaches. For example, cyclopropylethyl comprises an ethylbackbone with a cyclopropyl substituent. Except as described below, allbonds are identified in the chemical structure diagrams herein, exceptfor all bonds on some carbon atoms, which are assumed to be bonded tosufficient hydrogen atoms to complete the valency.

Compounds

In an aspect, the invention provides compounds which are capable ofselectively binding to and/or modulating a G12C mutant KRAS, HRAS orNRAS protein.

The compounds may modulate the G12C mutant KRAS, HRAS or NRAS protein byreaction with an amino acid. While not wishing to be bound by theory,the present applicants believe that, in some embodiments, the compoundsof the invention selectively react with the G12C mutant KRAS, HRAS orNRAS proteins by forming a covalent bond with the cysteine at the 12position of a G12C mutant KRAS, HRAS or NRAS protein. By binding to theCysteine 12, the compounds of the invention may lock the switch II ofthe G12C mutant KRAS, HRAS or NRAS into an inactive stage. This inactivestage may be distinct from those observed for GTP and GDP bound KRAS,HRAS or NRAS. Some compounds of the invention may also be able toperturb the switch I conformation. Some compounds of the invention mayfavor the binding of the bound KRAS, HRAS or NRAS to GDP rather than GTPand therefore sequester the KRAS, HRAS or NRAS into an inactive KRAS,HRAS or NRAS GDP state. Because effector binding to KRAS, HRAS or NRASis highly sensitive to the conformation of switch I and II, theirreversible binding of these compounds may disrupt KRAS, HRAS or NRASdownstream signaling.

Compounds of Structure (I)

In one embodiment of the present invention, compounds having activity asmodulators of a G12C mutant KRAS, HRAS or NRAS protein are provided, thecompounds have the following structure (I):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein:

A is N or CR′;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁷;

R′ is H, cyano, alkyl, cycloalkyl, amino, aminylalkyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, aminylalkoxy, alkylaminylalkoxy,alkylaminyl, alkylaminylalkyl, aminylalkylaminyl, carboxyalkyl,alkylcarbonylaminyl, aminylcarbonyl, alkylaminylcarbonyl oraminylcarbonylalkyl;

L² is a bond or alkylene;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, cyano, halo,hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkylaminyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy; C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl,C₁-C₆ alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring;

R^(5a) and R^(5b) are, at each occurrence, independently H, hydroxyl,halo or C₁-C₆ alkyl, or R^(5a) and R^(5b) join to form oxo;

R⁶ is amino, cyano, substituted alkyl, haloalkyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl; or substituted orunsubstituted: C₁-C₆ alkylphosphoryl, C₁-C₆ alkylphosphorylaminyl,cycloalkyl, heterocyclyl, aryl or heteroaryl when R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroarylaryl; or R⁶is methyl when R¹ is substituted aryl or substituted or unsubstitutedheteroarylaryl;

R⁷ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocyclyl;

m¹ and m² are each independently 1, 2 or 3;

n is an integer from 0 to 6;

X is a bond, —O—, —NR⁷— or —S—; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In some embodiments, each occurrence of alkyl, alkylene, aryl,heteroaryl, alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl,alkylphosphoryl, alkylphosphorylaminyl, aminylcarbonyl, alkylaminyl,haloalkyl, alkoxy, haloalkoxy; cycloalkyl, heterocyclylalkyl,heteroarylalkyloxy, heteroarylalkylaminyl and carbocyclic andheterocyclic rings is optionally substituted with one or moresubstituents unless otherwise specified.

In some embodiments of structure (I):

A is N, CH or C—CN;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, cyano, halo,hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl (e.g., CF₃),C₁-C₆ alkoxy, C₁-C₆ haloalkoxy; C₃-C₈ cycloalkyl, heterocycylalkyl,heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; or R^(3a) and R^(3b) join to form oxo, a carbocyclic orheterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; or R^(4a) and R^(4b) join to form oxo, a carbocyclic orheterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring;

R^(5a) and R^(5b) are, at each occurrence, independently H, hydroxyl,halo or C₁-C₆ alkyl, or R^(5a) and R^(5b) join to form oxo;

R⁶ is amino, cyano, substituted C₁-C₆ alkyl, haloalkyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl; or substituted orunsubstituted: C₁-C₆ alkylphosphoryl, C₁-C₆ alkylphosphorylaminyl,cycloalkyl, heterocyclyl, aryl or heteroaryl when R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroarylaryl; or R⁶is methyl when R¹ is substituted aryl or substituted or unsubstitutedheteroarylaryl;

R⁷ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocyclyl;

m¹ and m² are each independently 1, 2 or 3;

n is an integer from 0 to 6;

X is a bond, —O—, —NR⁷— or —S—; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In other embodiments of the compound of structure (I):

A is N;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, halo,hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl (e.g., CF₃),C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to forma carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring;

R^(5a) and R^(5b) are, at each occurrence, independently H, hydroxyl,halo or C₁-C₆ alkyl, or R^(5a) and R^(5b) join to form oxo;

R⁶ is amino, cyano, substituted C₁-C₆ alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl when R¹ is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroarylaryl; or R⁶ is methyl when R¹ issubstituted aryl or substituted or unsubstituted heteroarylaryl;

R⁷ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocycloalkyl;

m¹ and m² are each independently 1, 2 or 3;

n is an integer from 0 to 6;

X is a bond, —O—, —NR⁷— or —S—; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In some embodiments, R⁶ is amino, cyano, substituted C₁-C₆ alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl when R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroarylaryl; or R⁶is methyl when R¹ is substituted aryl or substituted or unsubstitutedheteroarylaryl.

In some different embodiments, A is N. In other embodiments, A is C—CN.In other embodiments, A is CH.

The structure of E is not particularly limited provided it is capable offorming a covalent bond with a nucleophile, such as the cysteine residueat position 12 of a KRAS, HRAS or NRAS G12C mutant protein. Accordingly,moieties which are capable of reaction with (e.g., by covalent bondformation) a nucleophile are preferred. In certain embodiments, E iscapable of reacting in a conjugate addition manner (e.g., 1.4-conjugateaddition) with an appropriately reactive nucleophile. In someembodiments, E comprises conjugated pi bonds such that delocalization ofelectrons results in at least one atom (e.g., a carbon atom) having apositive charge, partial positive charge or a polarized bond. In otherembodiments, E comprises one or more bonds wherein the electronegativityof the two atoms forming the bonds is sufficiently different such that apartial positive charge (e.g., by polarization of the bond) resides onone of the atoms, for example on a carbon atom. E moieties comprisingcarbon-halogen bonds, carbon-oxygen bonds or carbon bonds to variousleaving groups known in the art are examples of such E moieties.

In certain embodiments of the foregoing, E has the following structure:

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆ alkyl; and

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;

when

is a triple bond; then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In certain embodiments when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R⁹ andR¹⁰ join to form a carbocyclic or heterocyclic ring.

In some of the foregoing embodiments, Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂—or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR⁸ is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodiments R⁸ isH. In other embodiments, R⁸ is —CN. In other embodiments, R⁸ is —OH.

Accordingly, in some embodiments, the compound has the followingstructure (I′a):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR S(═O)₂—;

R^(8′) is H, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆ alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;and

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆ alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In other embodiments, the compound has one of the following structures(I′b), (I′c), (I′d) or (I′e):

In any of the foregoing embodiments of the compounds of structure (I),(I′a), (I′b), (I′c), (I′d) or (I′e), A is N. In some other of theforegoing embodiments of the compounds of structure (I), (I′a), (I′b),(I′c), (I′d) or (I′e), A is C—CN.

Without wishing to be bound by theory, Applicants believe correctselection of the R¹ substituent may play a part in the compounds'inhibitory activity (e.g., against KRAS, HRAS or NRAS G12C). In someembodiments, R¹ is aryl or heterocyclyl (e.g., heteroaryl or aliphaticheterocyclyl), each of which is optionally substituted with one or moresubstituents. In some embodiments, R¹ is capable of reversibleinteraction with KRAS, HRAS or NRAS G12C mutant protein. In someembodiments R¹ has high affinity towards KRAS, HRAS or NRAS and ishighly specific towards G12C KRAS, HRAS or NRAS. In some embodiments R¹is capable of hydrophobic interaction with KRAS, HRAS or NRAS G12C. Insome embodiments R¹ is able to form hydrogen bonds with various residuesof G12C KRAS, HRAS or NRAS protein.

In any of the foregoing embodiments, R¹ is aryl. For example in someembodiments R¹ is phenyl, and in other embodiments R¹ is naphthyl. R¹ issubstituted or unsubstituted. In some specific embodiments, R¹ issubstituted with one or more substituents. In some embodiments, R¹ issubstituted with halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl,aryl, heteroaryl, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy orC₁-C₆ alkylcarbonyloxy, or combinations thereof, wherein R is C₁-C₆alkyl. For example, in some embodiments R¹ is substituted with halo,hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy or C₁-C₆alkylcarbonyloxy, or combinations thereof. In different embodiemnts, R¹is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl,cyclopropryl, trifluoromethyl or methoxy, or combinations thereof. Insome even more embodiments, R¹ is substituted with fluoro, hydroxyl,methyl, isopropyl, trifluoromethyl or methoxy, or combinations thereof.

In some embodiments, R¹ has one of the following structures:

In some more specific embodiments, R¹ has one of the followingstructures:

In some specific embodiments, R¹ has one of the following structures:

In still different embodiments, R¹ has one of the following structures:

In some different embodiments of the foregoing compounds, R¹ isheteroaryl, for example a heteroaryl comprising nitrogen. In otherembodiments, R¹ is indazolyl, indolyl, benzoimidazole, benzotriazole orquinolinyl, for example indazolyl or quinolinyl. In more embodiments, R¹is heteroaryl which is substituted with one or more substituents. Forexample, in certain embodiments, R¹ is substituted with hydroxyl, haloor C₁-C₆ alkyl, or combinations thereof, for example hydroxyl or C₁-C₆alkyl.

In some more specific embodiments, R¹ has one of the followingstructures:

for example one of the following structures:

In some embodiments, R^(2a) and R^(2b) are each independently halo,haloalkyl, alkyl, or alkoxy. In some of the foregoing embodiments R^(2c)is H. In other of any of the foregoing embodiments, R^(2a) and R^(2b)are each halo. In some embodiments, R^(2a) is fluoro, chloro or methoxy.For example, in some embodiments R^(2a) is fluoro, and in otherembodiments, R^(2b) is chloro. In different embodiments, R^(2b) ischloro, fluoro or CF₃.

In some more specific embodiments, the compounds have the followingstructure (I′f):

For example, in even further different embodiments, the compounds haveone of the following structures (I′g) or (I′h):

In any of the foregoing embodiments of the compounds of structure (I′f),(I′g) or (I′h), A is N. In some other of the foregoing embodiments ofthe compounds of structure (I′f), (I′g) or (I′h), A is C—CN.

In some other embodiments of the foregoing, n is 0, X is a bond and R⁶is heterocyclyl. In some of these embodiments, R⁶ is azetidinyl,pyrrolidinyl, piperidinyl or morpholinyl. In other embodiments, R⁶ issubstituted, for example in some embodiments R⁶ is substituted withC₁-C₆ alkyl, C₁-C₆ alkylaminyl, heterocyclyl or spiro-heterocyclyl, orcombinations thereof. In some embodiments, R⁶ has one of the followingstructures:

In some other different embodiments, R⁶ has one of the followingstructures:

In some specific embodiments, R⁶ has one of the following structures:

In some specific embodiments, R⁶ has one of the following structure:

In some other different embodiments of the foregoing, n is an integerfrom 1 to 6, X is —O— and R⁶ is heterocyclyl or heteroaryl, providedthat R⁶ is not morpholinyl, piperazinyl, pyrrolidinyl or imidazolyl whenR¹ is indazolyl. In some of these embodiments, R⁶ is azetidinyl,pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl,pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl,thiomorpholinyl, or an oxidized analogue thereof, dioxolanyl, ortetrahydropyranyl. In some further these embodiments, R⁶ is azetidinyl,pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl,pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl,thiomorpholinyl, or an oxidized analogue thereof, or tetrahydropyranyl.In some other embodiments, R⁶ is substituted, for example substitutedwith oxo, cyano, halo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, heteroaryl, or combinations thereof. In some otherembodiments, R⁶ is substituted, for example substituted with oxo, cyano,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or combinationsthereof. In some different embodiments, n is 1. In some otherembodiments, n is 2. In some more different embodiments, n is 3. Inother different embodiments, R⁶ has one of the following structures:

In some specific embodiments, R⁶ has one of the following structures:

In some specific embodiments, R⁶ has one of the following structures:

In still more embodiments of the foregoing, n is an integer from 1 to 6,X is —NR⁷— and R⁶ is heterocyclyl or heteroaryl, provided that R⁶ is notN-methylimidazolyl when R¹ is indazolyl. In some of these embodiments,R⁶ is piperidinyl, pyridinyl, imidazolyl, pyrrolidinyl, pyrimidyl, orazetidinyl. In some other embodiments, R⁶ is piperidinyl, pyridinyl,imidazolyl, pyrrolidinyl, or azetidinyl. In other embodiments, R⁶ issubstituted, for example in some embodiments R⁶ is substituted withhalo, hydroxyl, C₁-C₆ alkyl C₃-C₈ cycloalkyl, or combinations thereof.In some different embodiments, n is 1. In some other embodiments, n is2. In some more different embodiments, n is 3. In various embodiments,R⁷ is H or methyl. In other more specific embodiments, R⁶ has one of thefollowing structures:

In other specific embodiments, R⁶ has one of the following structures:

In other specific embodiments, R⁶ has one of the following structures:

In still other embodiments, n is 0, X is —O— and R⁶ is cycloalkyl,heterocyclyl or heteroaryl, provided that R⁶ is not tetrahydropyranyl ortetrahydrofuranyl when R^(2a) is H and provided that R⁶ is notN-methylpyrazolyl when R¹ is indazolyl. In some of these embodiments, R⁶is cyclohexyl, oxetanyl, tetrahydropyranyl, pyrrolyl, pyrazolyl,azetidinyl, or piperidinyl. In other embodiments, R⁶ is cyclohexyl,oxetanyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, or piperidinyl. Incertain other embodiments, R⁶ is substituted, for example substitutedwith hydroxyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ haloalkyl, C₃-C₇cycloalkyl, C₁-C₆ alkylcarbonyl, heterocyclyl, or combinations thereof.In other embodiments, R⁶ is substituted with hydroxyl, C₁-C₆ alkyl,C₃-C₈ cycloalkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, C₁-C₆alkylcarbonyl, heterocyclyl, or combinations thereof. In some other morespecific embodiments, R⁶ has one of the following structures:

In other specific embodiments, R⁶ has one of the following structures:

In other specific embodiments, R⁶ has one of the following structures:

In still other embodiments, n is 0, X is —NR⁷— and R⁶ is a 3, 4, 6, 7 or8-membered heterocyclyl (e.g., 3, 4, 6, or 7-membered) or 3, 4, 6 or7-membered heteroaryl, provided that R⁶ is not tetrahydropyranyl orN-methylpiperidinyl when R¹ is indazolyl; or n is 0, X is —NR⁷— and R⁶is a 5-membered, oxygen-containing heterocyclyl and R¹ is aryl. Forexample, in some embodiments R⁶ is piperidinyl, tetrahydrofuranyl,tetrahydrothiopyranyl, or an oxidized analogue thereof,azabicyclo[3.2.1]octanyl, or tetrahydropyranyl. In some otherembodiments R⁶ is piperidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl,or an oxidized analogue thereof, or tetrahydropyranyl. In some furtherembodiments of the foregoing, R⁶ is substituted, for example substitutedwith hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,cycloalkylalky, heterocyclyl, C₁-C₆ alkylcarbonyl, heteroaryl, orcombinations thereof. In other embodiments, R⁶ is substituted withhydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl,cycloalkylalky, heterocyclyl, C₁-C₆ alkylcarbonyl, or combinationsthereof. In even more embodiments, R⁶ has one of the followingstructures:

In some specific embodiments, R⁶ has one of the following structures:

In some specific embodiments, R⁶ has one of the following structures:

In still other embodiments, R⁶ is substituted alkyl, for example C₁-C₆alkyl. In some of these embodiments R⁶ is substituted with onesubstituent selected from the group consisting of alkylaminylcarbonyl,C₂-C₆ dialkylaminyl, halo, C₁-C₆ monoalkylaminyl, heteroarylamino,heteroarylalkyloxy and alkylsulfonyl, for example, alkylaminylcarbonyl,C₂-C₆ dialkylaminyl, halo, C₁-C₆ monoalkylaminyl, heteroarylamino, andalkylsulfonyl, and wherein R⁶ optionally comprises one or moreadditional substituent. In further embodiments, R⁶ has one of thefollowing structures:

For example, one of the following structures:

In some embodiments, R⁶ has one of the following structures:

In some embodiments, R⁶ has one of the following structures:

In yet more embodiments, R⁶ is alkyl, for example C₁-C₆ alkyl,substituted with at least one hydroxyl and X is —O—.

In other embodiments, R⁶ is alkyl, for example C₁-C₆ alkyl, substitutedwith at least one hydroxyl and R¹ is heteroaryl. In other embodiments,R⁶ is alkyl, for example C₁-C₆ alkyl, substituted with at least onehydroxyl and R¹ is aryl or heteroaryl.

In still different embodiments, R⁶ is substituted C₂-C₆ alkyl, X is abond and n is 0. In some of these embodiments, R⁶ is substituted withdialkylaminyl.

In some embodiments, R⁶ is cyano. In other embodiments, R⁶ is amino. Inother embodiments, R⁶ is C₁-C₆ alkylphosphoryl, such as —P(═O)(CH₃)₂. Inother embodiments, R⁶ is C₁-C₆ alkylphosphoryaminyl, such as—NHP(═O)(CH₃)₂. In still other embodiments, R⁶ is perhalomethyl, such as—CF₃.

In still more embodiments, X is a bond, n is an integer from 1 to 3 andR⁶ is heteroarylalkyloxy or heteroarylalkylaminyl. For example, in someof these embodiments n is 1. In other embodiments, R⁶ ispyridinylalkyloxy, pyridinylalkylaminyl, pyrimidinylalkyloxy orpyrimidinylalkylaminyl. In other more specific embodiments

has one of the following structures:

In still other embodiments, X is NR⁷ and n is 1, wherein R^(5a) andR^(5b) join to form oxo. In further of these embodiments, R⁶ isheteroaryl, for example pyridinyl. In more specific embodiments,—X(CR^(5a)R^(5b))_(n)R⁶ has the following structure:

In some embodiments of the foregoing, X is a bond. In other embodiments,X is —O—. In different embodiments, X is —NR⁷—. In some other differentembodiments, X is —S—. In other different embodiments, X is a bond, n is1 and R^(5a) and R^(5b) join to form oxo.

In yet more of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl; and

R⁹ and R¹⁰ are each independently H, halo, cyano, carboxyl, C₁-C₆ alkyl,alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl,heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R⁹ and R¹⁰ join toform a carbocyclic, heterocyclic or heteroaryl ring.

In still other of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl; and

R¹⁰ is H, C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

The Q moiety is typically selected to optimize the reactivity (i.e.,electrophilicity) of E. In some of the foregoing embodiments Q is—C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—. In certain of theforegoing embodiments, Q is —C(═O)—. In other embodiments, Q is—S(═O)₂—. In still more embodiments, Q is —NR⁸C(═O)—. In still moredifferent embodiments, Q is —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodimentsR^(8′) is H. In other embodiments, R^(8′) is —CN. In other embodiments,R^(8′) is —OH.

In some of the foregoing embodiments, R⁸ is H. In other of theseembodiments, R⁸ is hydroxylalkyl, for example in some embodiments thehydroxylalkyl is 2-hydroxylalkyl.

In some of any one of the foregoing embodiments, at least one of R⁹ orR¹⁰ is H. For example, in some embodiments each of R⁹ and R¹⁰ are H.

In other of the foregoing embodiments, R¹⁰ is alkylaminylalkyl. In someof these embodiments, R¹⁰ has the following structure:

In other embodiments, R¹⁰ is hydroxylalkyl, such as 2-hydroxylalkyl.

In some other different embodiments of the foregoing embodiments, R⁹ andR¹⁰ join to form a carbocyclic ring. For example, in some of theseembodiments the carbocyclic ring is a cyclopentene, cyclohexene orphenyl ring. In other embodiments, the carbocyclic ring is acyclopentene or cyclohexene ring. In other embodiments, the carbocyclicring is a phenyl ring, for example a phenyl ring having the followingstructure:

In some of any of the foregoing embodiments E is an electrophile capableof bonding with a KRAS, HRAS or NRAS protein comprising G12C mutation.In some embodiments, the electrophile E is capable of forming anirreversible covalent bond with a G12C mutant KRAS, HRAS or NRASprotein. In some cases, the electrophile E may bind with the cysteineresidue at the position 12 of a G12C mutant KRAS, HRAS or NRAS protein.In various embodiments of any of the foregoing, E has one of thefollowing structures:

In some embodiments, E has one of the following structures:

In other embodiments of any of the foregoing, E has one of the followingstructures:

In different embodiments, E has one of the following structures:

In some cases E has one of the following structures:

wherein:

R⁸ is H or C₁-C₆alkyl;

R⁹ is H, cyano or C₁-C₆alkyl, or R⁹ joins with R¹⁰ to form a carbocycle;

R¹⁰ is H or C₁-C₆alkyl or R¹⁰ joins with R⁹ to form a carbocycle and

R^(10a) is H or C₁-C₆alkyl.

In some embodiments E is

In some embodiments E is

In some embodiments E is

In some of any of the foregoing embodiments, L¹ is a bond. In otherembodiments, L¹ is NR⁷. For example, in some of these embodiments, R⁷ isC₁-C₆alkyl. In other embodiments, L¹ is NH.

L² can be selected to provide proper spacing and/or orientation for theE group to form a bond with the KRAS, HRAS or NRAS protein. In some ofthe foregoing embodiments, L² is a bond. In other of the foregoingembodiments, L² is alkylene. In some embodiments, the alkylene issubstituted. In other embodiments the alkylene is unsubstituted. Forexample, in some embodiments L² is CH₂ or CH₂CH₂.

In certain embodiments, R^(3a) and R^(3b) are, at each occurrence,independently H, —OH, —NH₂, —CO₂H, halo, cyano, hydroxylalkly,aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl, and R^(4a) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H, —OH, hydroxylalkly, cyano, oraminylcarbonyl and R^(3b) and R^(4b) are H.

In certain other embodiments, R^(3a) and R^(4a) are H and R^(3b) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In any of the foregoing embodiments, at least one of R^(3a), R^(3b),R^(4a) or R^(4b) is H. In some embodiments, each of R^(3a), R^(3b),R^(4a) and R^(4b) are H.

In some embodiments, R^(3a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b), R^(4a) and R^(4b) are H.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H or C₁-C₆ alkyl. In some embodiments, atleast one of R^(3a), R^(4a), R^(3b) and R^(4b) is independently C₁-C₆alkyl, such as methyl. In some embodiments, one occurrence of R^(3a) isC₁-C₆ alkyl, such as methyl, and the remaining R^(3a) and each R^(4a) isH. In some other embodiments, two occurrences of R^(3a) are C₁-C₆ alkyl,such as methyl, and the remaining R^(3a) and each R^(4a) is H. In someother embodiments, one occurrence of R^(3a) and one occurrence of R^(4a)is independently C₁-C₆ alkyl, such as methyl, and the remaining R^(3a)and R^(4a) are each H.

In other embodiments, R^(4a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3a), R^(3b) and R^(4b) are H.

In other embodiments, R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b) joins with R^(4b) to form a carbocyclic or heterocyclic ring;

In still more embodiments, R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(4b) joins with R^(3b) to form a carbocyclic or heterocyclic ring.

In other embodiments, R^(3a) and R^(3b) join to form a carbocyclic orheterocyclic ring. In other embodiments, R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring.

In still other embodiments, R^(3a) or R^(4a) is aminylcarbonyl. Forexample, in certain embodiments, the aminylcarbonyl is

In other embodiments, R^(3a) or R^(4a) is cyano. In other embodiments,R^(3a) or R^(4a) is —OH. In other embodiments, R^(3a) or R^(4a) ishydroxylalkyl, for example hydroxylmethyl.

In some embodiments of any of the foregoing compounds (e.g., thecompounds of structures (I), (I′a), (I′b), (I′c), (I′d) or (I′e)), R¹ isaryl or heteroaryl and R^(2a), R^(2b) and R^(2c) are independentlyselected from H and halo, for example in some further embodiments R¹ isaryl or heteroaryl and R^(2a) and R^(2b) are independently selected fromhalo, such as chloro and fluoro, and R^(2c) is H. In some embodiments,R¹ is aryl or heteroaryl, R^(2a) is chloro, R^(2b) is fluoro and R^(2c)is H. In other embodiments R¹ is aryl or heteroaryl, one of R^(2a) orR^(2b) is halo, such as chloro or fluoro, and the other one of R^(2a) orR^(2b) is H.

In some embodiments of any of the compounds described herein, C₁-C₆haloalkyl is CF₃ (e.g., when one or more of R^(2a), R^(2b) or R^(2c) isC₁-C₆ haloalkyl).

In some embodiments m¹ is 1. In other embodiments m¹ is 2. In still moreembodiments, m¹ is 3. In different embodiments, m² is 1. In some otherembodiments, m² is 2. In yet still more embodiments, m² is 3.

In some other particular embodiments of any of the foregoing compounds,m¹ is 1, and m² is 1. In other embodiments, m¹ is 1 and, m² is 2. Instill other embodiments m¹ is 2, and m² is 2. In more embodiments, m¹ is1, and m² is 3.

In any of the foregoing embodiments, G¹ and G² are each independentlyselected from N and CH. In some embodiments, at least one of G¹ or G² isN. In some embodiments, each of G¹ and G² are N. In some embodiments,each of G¹ and G² are N and m¹ and m² are each 2. In some otherembodiments, at least one of G¹ or G² is CH. In other embodiments, eachof G¹ and G² are CH.

For example, in other embodiments the compounds have one of thefollowing structures (I′i) or (I′j):

wherein R¹, R^(2a), R^(2b), R^(2c), R^(5a), R^(5b), R⁶, X and n are asdefined according to any of the foregoing embodiments. In some morespecific embodiments of compounds (I′i) or (I′j), R¹ has one of thefollowing structures:

In any of the foregoing embodiments, A is N. In other of the foregoingembodiments, A is C—CN. In other of the foregoing embodiments, A is CH.

Some embodiments of the compounds include more than one stereoisomer.Other embodiments are directed to a single stereoisomer. In someembodiments the compounds are racemic (e.g., mixture of atropisomers),while in other embodiments the compounds are substantially a singleisomer, for example a substantially purified atropisomer.

In various different embodiments, the compound has one of the structuresset forth in Table 1 below. The compounds in Table 1 were each preparedand analyzed by mass spectrometry and/or ¹H NMR. Experimental massspectrometry data is included in Table 1. Exemplary synthetic proceduresare described in more detail below and in the Examples. General methodsby which the compounds may be prepared are provided below and indicatedin Table 1.

TABLE 1 Representative Compounds of Structure (I) No. Structure NameMethod [M + H]⁺ I-1

1-(2-(4-(4- acryloylpiperazin- 1-yl)-6-chloro- 8-fluoro- 7-(5-methyl-1H-indazol-4- yl)quinazolin-2- yloxy)ethyl) pyrrolidin-2-one A 578.1 I-2

(E)-1-(2-(6- chloro-4-(4-(4- (dimethylamino) but-2-enoyl)piperazin-1-yl)- 8-fluoro-7-(5- methyl-1H- indazol-4- yl)quinazolin-2-yloxy)ethyl) pyrrolidin-2-one A 635.3 I-3

1-(4-(6-chloro-8- fluoro-7-(2-fluoro- 6-hydroxyphenyl)- 2-(1-methylpiperidin-4- ylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 543.2 I-4

2-(4-(4- acryloylpiperazin- 1-yl)-6-chloro-8- fluoro-7-(5- methyl-1H-indazol-4- yl)quinazolin-2- yloxy)-N,N- dimethyl- acetamide A 552.2 I-5

1-(4-(6-chloro-8- fluoro-2-(2- hydroxyethyl- amino)-7-(5- methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one B 510.3I-6

1-(4-(6-chloro-8- fluoro-2-(2-(2- methyl-1H- imidazol-1-yl)ethoxy)-7-(5- methyl-1H- indazol-4-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one D 575.2 I-7

1-(4-(2-(2-(1H- imidazol-1- yl)ethoxy)-6- chloro-8-fluoro- 7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one D561.2 I-8

2-(4-(4- acryloyl- piperazin- 1-yl)-6-chloro- 8-fluoro- 7-(2-fluoro-6-hydroxyphenyl) quinazolin-2- yloxy)-N,N- dimethyl- acetamide A 532.1 I-9

2-(4-(4- acryloyl- piperazin-1-yl)- 6-chloro-2-(2- (dimethylamino)-2-oxoethoxy)-8- fluoroquinazolin- 7-yl)-3- fluorophenyl acrylate A 586.1I-10

1-(4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 560.2 I-11

4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(5- methyl-1H-indazol-4- yl)quinazoline- 2-carbonitrile G 476.2 I-12

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(1-(2,2,2-trifluoroethyl) piperidin-4- ylamino) quinazolin- 4-yl)piperazin-1-yl)prop-2- en-1-one B 631.3 I-13

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(tetrahydro-2H-pyran-4- yloxy)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en- 1-one A551.3 I-14

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A592.3 I-15

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)-2-((tetrahydro-2H- pyran-4-yl) methoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en- 1-one A 565.4 I-16

1-(2-(4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-2- yloxy)ethyl) pyrrolidin-2-one A558.2 I-17

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethylthio) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 576.2 I-18

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(tetrahydro-2H-pyran-4- yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A531.3 I-19

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(oxetan-3-yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A 503.2 I-20

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-4- ylamino)-8- fluoro-7-(5-methyl-1H- indazol-4- yl)quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one B 589.3 I-21

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-(2,2,2-trifluoroethyl) piperidin-4- ylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en- 1-one B 611.3 I-22

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-methyl-pyrrolidin-3- yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A530.2 I-23

1-(4-(6-chloro- 2-(3-(4,4- difluoro- piperidin-1-yl) azetidin-1-yl)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 605.2 I-24

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(3-morpholino- azetidin-1-yl) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 571.3 I-25

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-methyl-1H-pyrazol-4-yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A527.2 I-26

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-(2,2,2-trifluoroethyl) pyrrolidin-3- yloxy) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 598.3 I-27

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-(2,2,2-trifluoroethyl) piperidin-4- yloxy) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 612.4 I-28

(R)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 560.2 I-29

(S)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 560.2 I-30

1-(4-(6-chloro- 2-(2-(3,3- difluoro- pyrrolidin-1- yl)ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 580.3 I-31

(R)-1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 580.3 I-32

(S)-1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 580.3 I-33

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-((S)-3-methoxy- pyrrolidin-1-yl) ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en- 1-one A 574.2 I-34

1-(4-(6-chloro- 2-(2-(dimethyl- amino)ethyl)- 8-fluoro-7-(5- methyl-1H-indazol-4-yl) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one E 523.3I-35

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((1-(2,2,2-trifluoroethyl) piperidin-4-yl) methoxy) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 626.3 I-36

1-(4-(6-chloro- 2-(2-(3,3- difluoroazetidin- 1-yl)ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 566.3 I-37

1-(4-(6-chloro- 8-fluoro-7-(2- isopropylphenyl)- 2-(2-morpholino-ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A 568.3 I-38

1-(4-(6-chloro- 2-(2-(4,4- difluoro- piperidin-1-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 594.2 I-39

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- methoxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 574.3 I-40

1-(4-(6-chloro- 2-(2-(diethyl- amino)ethoxy)- 8-fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 546.3I-41

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(3-(4-methyl-piperazin-1- yl)azetidin-1- yl)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en-1-one A 584.3 I-42

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(4-isopropyl- piperazin-1-yl) ethoxy) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 601.3 I-43

1-(4-(2-(2- (azetidin-1-yl) ethoxy)-6- chloro-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 530.3I-44

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen-1-yl)-2-(2-(pyridin-2- yl)ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 585.2 I-45

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyridin-2- yl)ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one C 553.2 I-46

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2- morpholino-quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one B 548.2 I-47

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-morpholino-quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one B 516.1 I-48

1-(4-(6-chloro- 8-fluoro-2-(2- morpholino- ethoxy)-7-(2-(trifluoromethyl) phenyl) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 594.3 I-49

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(morpholine-4-carbonyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one F 544.3I-50

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin- 1-yl)-2- fluoroprop-2-en-1-one A 610.3 I-51

(S)-1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A592.3 I-52

(R)-1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A592.3 I-53

1-(4-(6-chloro- 2-(3-(dimethyl- amino)-2- hydroxy- propoxy)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one C 569.2 I-54

1-(4-(6-chloro- 8-fluoro-7-(3- methoxy- naphthalen-1- yl)-2-(2-(pyridin-2-yl) ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-oneC 599.2 I-55

1-(4-(6-chloro- 2-(3-(dimethyl- amino)azetidin- 1-yl)-8-fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 529.2 I-56

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-((R)-3-hydroxy- pyrrolidin-1-yl) ethylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 560.2 I-57

4-(2-(4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(3- hydroxy-naphthalen-1- yl)quinazolin- 2-yloxy)ethyl) morpholin-3-one C 605.3*I-58

1-(4-(6-chloro- 2-(3-(dimethyl- amino)-2- hydroxy- propoxy)-8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)quinazolin- 4-yl)piperazin-1-yl)prop-2- en-1-one C 581.2 I-59

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)-2- (1-methyl-piperidin-4- yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A564.3 I-60

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)-2-fluoroprop-2-en-1-one A 578.4 I-61

1-(4-(6-chloro- 8-fluoro-2-(2- fluoroethyl- amino)-7-(3- hydroxy-naphthalen-1- yl)quinazolin- 4-yl)piperazin- 1-yl)prop-2- en-1-one B524.3 I-62

1-(4-(6-chloro- 2-(3-(3,3- difluoro- pyrrolidin-1-yl) propoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 594.3 I-63

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(4-hydroxy-cyclohexyloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A 545.2I-64

1-(4-(2-(1H- pyrazol-4- yloxy)-6-chloro- 8-fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 513.2I-65

(E)-1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin- 1-yl)-4- (dimethyl-amino)but- 2-en-1-one A 649.4 I-66

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(tetrahydro-2H-dioxothio- pyran-4- ylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 578.2 I-67

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-dioxothio-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A608.3 I-68

4-(4- acryloyl- piperazin-1- yl)-6-chloro- 8-fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazoline-2- carbonitrile G 456.2 I-69

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen-1- yl)-2-(tetrahydro- 2H-pyran-4- ylamino) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 562.3 I-70

1-(4-(2-(1- acetyl- piperidin-4- ylamino)-6- chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 571.3 I-71

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(tetrahydro- furan-3- ylamino) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 548.3 I-72

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-4- ylamino)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 569.3 I-73

2-chloro-1-(4- (6-chloro-8- fluoro-7-(3- hydroxy- naphthalen-1-yl)-2-(2- morpholino- ethoxy) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 626.2 I-74

(E)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)-4-(dimethyl-amino)but- 2-en-1-one A 617.3 I-75

1-(4-(6-chloro- 2-(1-cyclo- propylpiperidin- 4-ylamino)- 8-fluoro-7-(3-hydroxy- naphthalen-1- yl)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en-1-one B 601.3 I-76

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(4-fluoro-piperidin-1-yl) ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 576.3 I-77

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen-1- yl)-2-(1-isopropyl- piperidin-4- ylamino) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 603.4 I-78

(S)-1-(4-(6- chloro-2-(1- cyclopropyl- piperidin-4- ylamino)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 569.3 I-79

(R)-1-(4-(6- chloro-2-(1- cyclopropyl- piperidin-4- ylamino)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 569.3 I-80

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-4- ylamino)-8- fluoro-7-(2-hydroxy-6- methylphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 565.3 I-81

(S)-1-(4-(6- chloro-2-(1- cyclopropyl- piperidin-4- ylamino)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one B 589.4 I-82

(R)-1-(4-(6- chloro-2-(1- cyclopropyl- piperidin-4- ylamino)-8-fluoro-7-(5- methyl-1H- indazol-4- yl)quinazolin- 4-yl)piperazin-1-yl)prop-2- en-1-one B 589.3 I-83

1-(4-(6-chloro- 8-fluoro-2-(2- hydroxyethoxy)- 7-(3-hydroxy-naphthalen-1-yl) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A523.7 I-84

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-isopropyl-piperidin-4- ylamino) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-oneB 571.4 I-85

4-(4-acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazoline-2- carboxamide G 474.3 I-86

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(methyl-amino)ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A 504.2I-87

(S)-1-(4-(6- chloro-2-(2- (diethylamino) ethoxy)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 546.4 I-88

(R)-1-(4-(6- chloro-2-(2- (diethylamino) ethoxy)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 546.4 I-89

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(6-methyl-pyridin-2-yl) ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-oneA 566.3 I-90

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(4-methyl-piperazine-1- carbonyl) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one F 557.3 I-91

1-(4-(6-chloro- 7-(2,3- difluoro-6- hydroxyphenyl)- 8-fluoro-2-(2-morpholino- ethoxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one A578.1 I-92

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-methyl-piperidin-4- yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one C544.2 I-93

1-(4-(6-chloro- 8-fluoro-7-(3- hydroxy- naphthalen- 1-yl)-2-(1- methyl-piperidin-4- yloxy) quinazolin-4- yl)piperazin-1- yl)prop-2-en- 1-one C576.2 I-94

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-4- yloxy)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one C 570.2 I-95

(S)-1-(4-(6- chloro-2-(2- (dimethylamino) ethoxy)-8- fluoro-7-(3-hydroxy- naphthalen-1- yl)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en-1-one A 550.3 I-96

(R)-1-(4-(6- chloro-2-(2- (dimethylamino) ethoxy)-8- fluoro-7-(3-hydroxy- naphthalen-1-yl) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one A 550.3 I-97

(S)-1-(4-(6- chloro-2- (2-(3,3- difluoro- pyrrolidin-1- yl)ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4- yl)piperazin-1-yl)prop-2-en- 1-one A 580.3 I-98

(R)-1-(4-(6- chloro-2- (2-(3,3- difluoro- pyrrolidin-1- yl)ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 580.3 I-99

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((6-methyl-pyridin-2-yl) methoxy) quinazolin-4-yl) piperazin-1- yl)prop-2-en- 1-oneA 552.3 I-100

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(5-fluoro-pyridin-2-yl) ethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A570.3 I-101

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((2-methyl-pyrimidin-5- yl)methoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 553.4 I-102

(R)-1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyridin-2- yl)ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 552.3 I-103

(S)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyridin-2- yl)ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 552.3 I-104

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((6-methyl-pyridin-3-yl) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-oneA 552.4 I-105

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(pyrimidin-2-ylmethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 539.3I-106

1-(4-(6-chloro- 2-(3-(dimethyl- amino)azetidin- 1-yl)-8-fluoro-7-(3-hydroxy- naphthalen-1-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 561.3 I-107

1-(4-(6-chloro- 2-(2-(3,3- difluoro- azetidin-1-yl) ethoxy)-8-fluoro-7-(3- hydroxy- naphthalen-1-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 598.4 I-108

1-(4-(6-chloro- 8-fluoro-7-(6- hydroxy- quinolin-8-yl)- 2-(2-morpholino-ethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 593.4 I-109

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(oxazol-2-ylmethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 528.2I-1I-10

1-(4-(6-chloro- 2-(1-(cyclopropyl- methyl)piperidin- 4-ylamino)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 583.3 I-111

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(6-methyl-pyridin-3-yl) ethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A566.3 I-112

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(pyridin-2-ylmethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 538.3I-113

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(methyl-sulfonyl) ethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A552.2 I-114

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(3-fluoro-pyridin-2-yl) ethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A570.3 I-115

1-(4-(2-(1- acetylpiperidin- 4-yloxy)-6- chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 572.2 I-116

(S)-1-(4-(6- chloro-2-(3- (dimethylamino) azetidin-1-yl)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 529.2 I-117

(R)-1-(4-(6- chloro-2-(3- (dimethylamino) azetidin-1-yl)- 8-fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 529.2 I-118

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((2-methoxy-pyrimidin-5-yl) methoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 569.2 I-119

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(pyridazin-3-ylmethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 539.2I-120

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-3- ylamino)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 569.3 I-121

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-isopropyl-piperidin-3- ylamino) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one B571.3 I-122

6-((4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-2- yloxy)methyl) picolinonitrile A 563.2 I-123

1-(4-(6-chloro- 2-(2,2- difluoro-2- (pyridin-2-yl) ethoxy)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 609.2 I-124

1-(4-(6-chloro- 2-(2,2- difluoro-2- (pyridin-2-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 589.2 I-125

(S)-1-(4-(6- chloro-2- (2-(3,3- difluoro- azetidin-1-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 566.6 I-126

(R)-1-(4-(6- chloro-2- (2-(3,3- difluoro- azetidin-1-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 566.6 I-127

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(pyridazin-4-ylmethoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 539.6I-128

1-(4-(6-chloro- 2-(1-(cyclo- propylmethyl) piperidin-4- ylamino)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 603.4 I-129

5-((4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-2- yloxy)methyl) picolinonitrile A 563.3 I-130

1-(4-(6-chloro- 2-(2-(diethyl- amino)ethoxy)- 8-fluoro-7-(5- methyl-1H-indazol-4-yl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 566.20I-131

1-(4-(6-chloro- 2-(3-(diethyl- amino)azetidin- 1-yl)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 557.4 I-132

1-(4-(6-chloro- 2-(1-cyclobutyl- piperidin-4- ylamino)-8- fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 603.4 I-133

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(1-(2,2,2-trifluoroethyl) piperidin-3- ylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 611.8 I-134

1-(4-(6-chloro- 2-(1-(cyclopropyl- methyl)piperidin- 3-ylamino)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 583.4 I-135

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyrimidin- 2-ylamino)ethyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one H 552.7 I-136

1-(4-(6-chloro- 8-fluoro-2-(1- isopropyl- piperidin-4- ylamino)-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 591.4 I-137

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(1-(oxetan-3-yl)piperidin- 4-ylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 605.4 I-138

1-(4-(6-chloro- 2-(1-cyclopropyl- piperidin-4- ylamino)-8- fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 590.2 I-139

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)-2-(2-(pyrimidin- 2-yl)ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 574.2 I-140

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyrimidin- 2-yl)ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 554.1 I-141

1-(4-(6-chloro- 2-(2-(3,3- difluoro- azetidin-1-yl) ethylamino)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 585.2 I-142

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(2-(pyridin-2-yl) ethylamino) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one D571.2 I-143

1-(4-(6-chloro- 2-(2-(3,3- difluoro- azetidin-1-yl) ethylamino)-8-fluoro-7- (2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 565.2 I-144

1-(4-(6-chloro- 2-(3- (diethylamino) azetidin-1-yl)- 8-fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 577.2 I-145

1-(4-(6-chloro- 2-(2-(3,3- difluoro- azetidin-1-yl) ethoxy)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 586.2 I-146

1-(4-(6-chloro- 2-(2-(3,3- difluoro- pyrrolidin-1-yl) ethoxy)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one C 600.2 I-147

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(pyrrolidin-1- yl)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en- 1-one B500.1 I-148

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-oxa-6-azaspiro[3.3] heptan-6-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 528.2 I-149

1-(4-(6-chloro- 2-(3-(dimethyl- amino)-3- methyl- azetidin-1-yl)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 543.2 I-150

1-(4-(6-chloro- 2-((1-cyclopropyl- piperidin-4-yl) methylamino)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 583.4 I-151

l-(4-(6-chloro- 2-(2-(diethyl- amino) ethylamino)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 545.4 I-152

1-(4-(6-chloro- 8-fluoro-2-(3- (methoxy- methyl) azetidin-1-yl)-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 551.2 I-153

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyridin-2- yl)ethylamino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 551.2 I-154

1-(4-(6-chloro- 7-(2-fluoro-6- hydroxyphenyl)- 2,8-dimethoxy-quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one I 473.2 I-155

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(6-oxa-2-azaspiro[3,4] octan-2-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 542.2 I-156

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(6-oxa-2-azaspiro[3,4] octan-2-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 562.2 I-157

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-(6-methyl-2,6-diazaspiro [3.3]heptan- 2-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 561.2 I-158

1-(4-(6-chloro- 8-fluoro-2-((1- (3-fluoropyridin- 2-yl)azetidin-3-yl)methoxy)-7- (5-methyl-1H- indazol-4-yl) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one C 632.2 I-159

1-(4-(6-chloro- 2-(3-((dimethyl- amino)methyl) azetidin-1-yl)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 564.3 I-160

1-(4-(6-chloro- 2-((1-cyclo- propyl- piperidin-4-yl) methylamino)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-l-yl)prop-2-en-1-one B 603.3 I-161

1-(4-(6-chloro- 2-(2-(diethyl- amino) ethylamino)-8- fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 585.3 I-162

1-(4-(2-([1,3′- biazetidin]-1′- yl)-6-chloro- 8-fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one J 541.30I-163

1-(4-(2-((1,3- dioxolan-2- yl)methoxy)- 6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 533.10 I-164

1-(4-(2-((1,3- dioxolan-2- yl)methoxy)-6- chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 553.15 I-165

2-(4-((4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl) quinazolin-2-yl) amino) piperidin-1-yl)acetonitrile B 588.35 I-166

1-(4-(6-chloro- 2-(3-(4- cyclopropyl- piperazin-1-yl) azetidin-1-yl)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one J 610.35 I-167

1-(4-(6-chloro- 2-((1-(2,2- difluoroethyl) piperidin-4-yl) amino)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 613.35 I-168

1-(4-(6-chloro- 2-(2-(4- cyclopropyl- piperazin-1-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one K 599.30 I-169

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-((2-(pyrimidin-2- yl)ethyl) amino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one D 572.2 I-170

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)- 2-((1-(pyrimidin-2- yl)azetidin-3- yl)methoxy) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one C 614.2 I-171

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((2-(pyrimidin-2- yl)ethyl)amino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 552.1 I-172

1-(4-(6-chloro- 2-((1-cyclopropyl- piperidin-4-yl) methoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one K 584.25 I-173

1-(4-(6-chloro- 8-fluoro-2-((1- isopropyl- azetidin-3-yl) amino)-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 563.35 I-174

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-isopropyl- azetidin-3-yl) amino) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one J 543.30 I-175

1-(4-(2-amino- 6-chloro-8- fluoro-7-(2- fluoro-6- hydroxyphenyl)quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one J 446.10 I-176

1-(4-(6-chloro- 2-(3-(4- cyclopropyl- piperazin-1-yl) azetidin-1-yl)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 630.35 I-177

1-(4-(2-((1- (tert-butyl) piperidin-4-yl) amino)-6- chloro-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 605.35 I-178

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-isopropyl- azetidin-3-yl) oxy)quinazolin- 4-yl)piperazin-1-yl)prop-2-en- 1-one K 544.25 I-179

1-(4-(6-chloro- 2-(3,3-difluoro- [1,3′-biazetidin]- 1′-yl)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one J 577.20 I-180

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(2-(1-isopropyl- piperidin-4-yl) ethoxy) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one K 600.35 I-181

N-(4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-2-yl)- 2-methyliso- nicotinamide ??? 565.10I-182

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-(pyrimidin- 2-yl)azetidin-3- yl)amino) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one B 579.1 I-183

1-(4-(6-chloro- 2-(2-(diethyl- amino)ethoxy)- 8-fluoro-7-(6- methyl-1H-indazol-7-yl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one A 566.30I-184

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)-2-((1-(pyrimidin- 2-yl)piperidin-4- yl)amino) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one D 627.2 I-185

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-(tetrahydro- 2H-pyran-4-yl) azetidin-3-yl) amino) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one A 585.25 I-186

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-(tetrahydro- 2H-pyran-4-yl) azetidin-3- yl)oxy) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one K 586.25 I-187

1-(4-(6-chloro- 8-fluoro-7-(5- methyl-1H- indazol-4-yl)-2-((1-(pyrimidin- 2-yl)azetidin- 3-yl)amino) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one D 599.2 I-188

1-(4-(6-chloro- 2-((8- cyclopropyl-8- azabicyclo[3.2.1] octan-3-yl)amino)-8- fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one B 615.35 I-189

1-(4-(2-amino- 6-chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one B 466.15 I-190

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-((1-(pyrimidin- 2-yl)piperidin-4- yl)amino) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one B 607.2 I-191

1-(4-(2-amino- 6-chloro-8- fluoro-7-(3- hydroxy- naphthalen-1-yl)quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one B 478.25 I-192

1-(4-(6-chloro- 2-(2-(1- cyclopropyl- piperidin-4-yl) ethoxy)-8-fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one K 598.30 I-193

1-(4-(6-chloro- 8-fluoro-2-((1- isopropyl- piperidin-4-yl) oxy)-7-(5-methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 592.2 I-194

(S)-1-(4-(6- chloro-2-((1- cyclopropyl- piperidin-4-yl) oxy)-8-fluoro-7-(6- methyl-1H- indazol-7-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 590.40 I-195

1-(4-(6-chloro- 2-((1-cyclopropyl- piperidin-4-yl) oxy)-8- fluoro-7-(6-methyl-1H- indazol-7-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 590.40 I-196

1-(4-(6-chloro- 2-((1-cyclo- propylpiperidin- 4-yl)amino)-8-fluoro-7-(6- methyl-1H- indazol-7-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one B 589.45 I-197

4-(4-acryloyl- piperazin-1-yl)- 6-chloro-2-(3- (dimethyl- amino)azetidin-1-yl)- 8-fluoro-7- (2-fluoro-6- hydroxyphenyl) quinoline-3-carbonitrile P 553.35 I-198

1-(4-(6-chloro- 2-(2-(3- (dimethyl- amino)-3- methyl- azetidin-1-yl)ethyl)-8- fluoro-7-(2- fluoro-6- hydroxyphenyl) quinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one E 571.2 I-199

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-((pyridin-2-ylamino)methyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one L537.30 I-200

1-(4-(6-chloro- 2-(2-(3,3- difluoro- azetidin-1-yl) ethyl)-8-fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one E 550.15 I-201

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)-2-(2-(pyridin-2- ylamino)ethyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one H 551.25 I-202

4-(4- acryloyl- piperazin-1-yl)- 6-chloro-2-((1- cyclopropyl-piperidin-4- yl)amino)-8- fluoro-7-(5- methyl-1H- indazol-4-yl)quinoline-3- carbonitrile P 613.4 I-203

1-(4-(6-chloro- 2-((1-cyclopropyl- piperidin-4-yl) methoxy)-8-fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one A 604.45 I-204

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(trifluoro-methyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one M 499.25 I-205

1-(4-(6-chloro- 2-(dimethyl- phosphoryl)-8- fluoro-7-(2- fluoro-6-hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one N 507.15I-206

1-(4-(6-chloro- 2-(2-(dimethyl- phosphoryl) ethoxy)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one K 551.15 I-207

N-(2-(4-(4- acryloyl- piperazin-1-yl)- 6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-2- yloxy)ethyl)- P,P-dimethyl-phosphinic amide K 566.3 I-208

1-(4-(6-chloro- 2-(2-(dimethyl- phosphoryl) ethylamino)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one J 550.25 I-209

1-(4-(6-chloro- 2-((dimethyl- phosphoryl) methyl)-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one O 521.20 I-210

1-(4-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxyphenyl)- 2-(((3-fluoro-pyridin-2-yl) methoxy) methyl) quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one Q 569.6 *[M − H]⁻

In various different embodiments of any of the embodiments of thecompounds of structure (I), the compounds illustrated in Table 2 areexcluded from the invention.

TABLE 2 Compounds Excluded From Certain Embodiments No. Structure Name2-1

1-(4-(6-chloro-8-fluoro-2- (2-hydroxyethylamino)-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one 2-2

1-(4-(6-chloro-2-(2- (dimethylamino)ethyl- amino)-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1-yl)prop- 2-en-1-one2-3

1-(4-(6-chloro-2- ((dimethylamino)methyl)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-4

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydrofuran-3-yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-5

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1H-pyrazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-6

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1H-pyrazol-5-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-7

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-8

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydro-2H-pyran-3-yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-9

1-(4-(2-amino-6-chloro-7- (5-methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-10

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-methyl-1H-pyrazol-4- ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-11

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-12

1-(4-(6-chloro-2-(3- (dimethylamino)propoxy)- 7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-13

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydrofuran-3-ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-14

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(thiazol-5-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-15

(E)-1-(4-(6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4- yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one2-16

1-(4-(6-chloro-2-(3- (dimethylamino)propoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-17

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one 2-18

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(2-morpholino-ethoxy)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one 2-19

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(tetrahydrofuran-3- ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-20

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1- yl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-21

1-(4-(6-chloro-8-fluoro-2- (2-(1-methyl-1H- imidazol-2-yl)ethylamino)-7-(5- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-22

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-23

1-(4-(6-chloro-2-(2- (dimethylamino)ethyl- amino)-8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one2-24

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(2,2,2-trifluoro- ethylamino)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one 2-25

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(3-morpholino-propoxy)quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one 2-26

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(2-(pyrrolidin-1- yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-27

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl)-2-(1-methylpyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-28

1-(4-(6-chloro-2-((2- (dimethylamino)ethyl) (methyl)amino)-8-fluoro-7-(3-hydroxynaphthalen- 1-yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one 2-29

l-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin- 4-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-30

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl)-2-(3,3,3-trifluoro- propylamino)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one 2-31

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(tetrahydro-2H-pyran-4- ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-32

N-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloro-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinazolin-2- yloxy)ethyl)acetamide 2-33

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)-2-methylpiperazin-1- yl)prop-2-en-1-one2-34

1-(4-(6-chloro-8-fluoro-2- (2-(1-methyl-1H- imidazol-2-yl)ethoxy)-7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one 2-35

1-(4-(6-chloro-2-((2- (dimethylamino)ethyl) (methyl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one 2-36

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(1-methylpyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one 2-37

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(2-(4-methylpiperazin-1- yl)ethoxy)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one 2-38

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one2-39

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-methyl-1H-pyrazol-4- yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-40

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazoline-2- carbonitrile 2-41

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(methylamino)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one

The following General Reaction Schemes illustrate exemplary methods ofmaking compounds of compounds of structure (I):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein R¹, R^(2a), R^(2b), R^(2c), R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), R⁶, A, G¹, G², L¹, L², m¹, m², n, X and E are as definedherein. It is understood that one skilled in the art may be able to makethese compounds by similar methods or by combining other methods knownto one skilled in the art. It is also understood that one skilled in theart would be able to make, in a similar manner as described below, othercompounds of structure (I) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention.

Embodiments of the compound of structure (I) (e.g., compound A-13) canbe prepared according to General Reaction Scheme 1 (“Method A”), whereinR¹, R^(5a), R^(5b), R⁶, R⁹, R¹⁰ and n are as defined herein. Referringto General Reaction Scheme 1, compounds of structure A-1 are purchasedfrom commercial sources and reduced under appropriate conditions to formaniline A-2. A-2 is then treated with 2,2,2-trichloroethane-1,1-diol andsodium sulfate to yield A-3, which is subsequently cyclized by treatmentwith concentrated sulfuric acid. Ring-opening oxidation of A-4 thenyields A-5, which can be optionally chlorinated to yield A-6 when achloro substituent in the R^(2b) position is desired. Reaction of A-6with urea yield A-7, which is then chlorinated to yield quinazoline A-8.A-8 is then reacted with mono-boc protected piperazine to yield A-9.Reaction of A-9 with an appropriately-substituted alcohol provides A-10.The desired R¹ substituent may then be added by way of Suzuki couplingto yield A-11. Removal of the boc protecting group, followed by reactionwith an appropriately substituted acryloyl chloride yields the desiredcompound A-13.

Alternatively, embodiments of the compound of structure (I) (e.g.,compound B-3) can be prepared according to General Reaction Scheme 2(“Method B”), wherein R¹, R^(5a), R^(5b), R⁶, R⁷, R⁹, R¹⁰ and n are asdefined herein. Compound A-9 is prepared according to the procedures ofGeneral Reaction Scheme 2. Reaction of A-9 with an appropriatelysubstituted amine yields B-1. Suzuki coupling of B-1 with anappropriately substituted boronic acid yields B2. B-3 is then preparedin a manner analogous to the procedures of General Scheme 1.

Other embodiments of the compound of structure (I) (e.g., compound C-2)can be prepared according to General Reaction Scheme 3 (“Method C”),wherein R¹, R^(5a)R^(5b), R⁶, R⁹, R¹⁰ and n are as defined herein.Method C is analogous to Method A, except the order of some syntheticsteps are reversed. Specifically, A-10 is prepared according to Generalreaction Scheme 1. The boc protecting group is then removed and the freeamine is reacted with an appropriated acryloyl chloride to yield C-1.Finally, Suzuki coupling with an appropriate boronic acid yields thedesired C-2.

Other embodiments of the compound of structure (I) (e.g., compound D-2)can be prepared according to General Reaction Scheme 4 (“Method D”),wherein R¹, R^(5a)R^(5b), R⁶, R⁷, R⁹, R¹⁰ and n are as defined herein.General Reaction Scheme 4 provides an alternate route to compounds, suchas D-2. Compound B-1, which is prepared according to General ReactionScheme 2, is first deprotected, and then reacted with an appropriateacryloyl chloride. Suzuki chemistry then provides the desired compoundD-2.

Other embodiments of the compound of structure (I) (e.g., compound E-7)can be prepared according to General Reaction Scheme 5 (“Method E”),wherein R¹, R⁹ and R¹⁰ are as defined herein, and R^(a) and R^(b) areeach independently C₁-C₆ alkyl. As shown in General Reaction Scheme 5,compound A-6 from General reaction Scheme 1 is esterified to form E-1,which is then cyclized to form quinazoline E-2. Treatment of E-2 withphosphorous trichloride yields E-3, which is then reacted with mono-bocpiperazine to form E-4. Reaction of E-4 with an appropriatelysubstituted amine, followed by Suzuki reaction to install the desired R¹substituent, yields E-6. Compound E-7 is then prepared according tomethods described above.

Other embodiments of the compound of structure (I) (e.g., compound F-10)can be prepared according to General Reaction Scheme 6 (“Method F”),wherein R¹, R⁹ and R¹⁰ are as defined herein, and R^(a) and R^(b) jointo form heterocyclyl. Compound E-1 is first cyclized to form quinazolineF-1, which is subsequently chlorinated to provide F-2. Reaction of F-2with mono-boc piperazine yields F-3. F-3 is then converted to alcoholF-5 via a two-step process by way of intermediate acetate F-4. Oxidationof F-5 to aldehyde F-6, followed by further oxidation with sodiumperchlorate yields F-7. Suzuki reaction then provides the desired R¹substituted compound F-8. F-10 is produced from F-8 in a manneranalogous to that described with respect to General Reaction Scheme 5above.

Other embodiments of the compound of structure (I) (e.g., compound G-3or G-4) can be prepared according to General Reaction Scheme 7 (“MethodG”), wherein R¹, R⁹ and R¹⁰ are as defined herein. As shown in GeneralReaction Scheme 7, carboxylic acid F-8, prepared according to GeneralReaction Scheme 6, is converted to amide G-1. G-1 is converted to G-3following the general procedures outlined above. If desired, compoundG-3 is converted to nitrile G-4 by reaction with trifluoroacetic acidanhydride.

Other embodiments of the compound of structure (I) (e.g., compound H-10)can be prepared according to General Reaction Scheme 8 (“Method H”),wherein R¹, R⁹ and R¹⁰ are as defined herein above and R^(a) isheteroaryl. Referring to General Reaction Scheme 8, H-1 is purchasedfrom commercial sources or prepared according to known procedures.Suzuki coupling provides the desired R¹ substituent in compound H-2,which can then be chlorinated to H-3 followed by cyclization toquinazoline H-4. Chlorination of H-4 followed by reaction with mono-bocpiperazine provides H-6. H-6 is alkylated to provide H-7 which thenundergoes amination to yield H-8. Reaction of H-8 with an appropriatelyactivated R_(a) moiety, provides H-9. Removal of the N-protecting groupsand acylation of the free piperazine nitrogen provides the desiredcompound H-10.

Other embodiments of the compound of structure (I) (e.g., compound I-3)can be prepared according to General Reaction Scheme 9 (“Method I”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 9, compound A-9 is treated with sodium methoxide toprovide I-1, which is converted to I-2 under Suzuki conditions. Removalof the Boc protecting group, followed by Shotten-Baumann reactionprovides I-3.

Other embodiments of the compound of structure (I) (e.g., compound J-3)can be prepared according to General Reaction Scheme 10 (“Method J”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 10, compound H-6 is prepared according to the aboveprocedures and reacted with an appropriate nitrogen-containingheterocycle or heteroaryl (represented by J-1) to obtain J-2. J-2 isthen treated in a manner analogous to the above procedures to obtainJ-3.

Other embodiments of the compound of structure (I) (e.g., compound K-3)can be prepared according to General Reaction Scheme 11 (“Method K”),wherein R¹, R⁹, R¹⁰ and n are as defined herein above. Referring toGeneral Reaction Scheme 11, compound H-6 is prepared according to theabove procedures and reacted with an appropriate hydroxyl oralkylhydroxyl-substituted cycloalkyl, aryl, heterocycle or heteroarly(represented by K-1, where A is a cycloalkyl, arly, heterocycl orheteroaryl) to obtain K-2. K-2 is then treated in a manner analogous tothe above procedures to obtain K-3.

Other embodiments of the compound of structure (I) (e.g., compound L-9)can be prepared according to General Reaction Scheme 12 (“Method L”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 12, compound L-1 is prepared according to proceduresanalogous to those above (e.g., Suzuki reaction) or prepared accordingto methods known in the art. L-1 is methylated, for example with methyliodoide, to form L-2. Ring closure of L-2 yields L-3, which can then bechlorinated with an appropriate reagent, such as POCl₃. Reaction of L-4with boc-protected piperazine yields L-5. Conversion of L-5 to thecorresponding azide, followed by azide reduction yields L-6. Reaction ofL-6 with an appropriate heteroaryl or heterocyclic N-oxide (representedby L-7) yields L-8, which is then treated in a manner analogous to theabove procedures to obtain L-9.

Other embodiments of the compound of structure (I) (e.g., compound M-3)can be prepared according to General Reaction Scheme 13 (“Method M”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 13, compound L-1 is reacted with trifluoracetamide toform M-1. M-1 is reacted with Boc-protected piperazine to yield M-2,which is then treated in a manner analogous to the procedures of Generalreaction Scheme 1 to obtain M-3.

Other embodiments of the compound of structure (I) (e.g., compound N-2)can be prepared according to General Reaction Scheme 14 (“Method N”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 14, compound H-6 is prepared as described above andphosphorylated under appropraite conditions to yield N-1, which is thentreated in a manner analogous to the above procedures to obtain N-2.

Other embodiments of the compound of structure (I) (e.g., compound 0-2)can be prepared according to General Reaction Scheme 15 (“Method O”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 15, compound L-5 is prepared as described above andphosphorylated under appropraite conditions to yield O-1, which is thentreated in a manner analogous to the above procedures to obtain O-2.

Other embodiments of the compound of structure (I) (e.g., compound P-3)can be prepared according to General Reaction Scheme 16 (“Method P”),wherein R¹, R^(5a), R^(5b), R⁶, R⁹, R¹⁰ and n are as defined hereinabove. Referring to General Reaction Scheme 16, compound L-1 is preparedas described above and treated with bis(trichloromethyl) carbonate toform 1H-benzo[d][1,3]oxazine-2,4-dione P-1. P-1 may then be treated withethyl cyanoacetate to form P-2. P-2 is then converted to variousembodiments of structure (I) according to the general proceduresdescribed herein.

Other embodiments of the compound of structure (I) (e.g., compound Q-3)can be prepared according to General Reaction Scheme 17 (“Method Q”),wherein R¹, R⁹ and R¹⁰ are as defined herein above and R is asubstituted or unsubstituted alkyl. Referring to General Reaction Scheme17, compound F-3 is treated with alcohol ROH to provide Q-1, which isconverted to Q-2 under Suzuki conditions. Desired compound Q-3 is thenprepared according to the general methods described above.

Compounds of Structure (II)

In another embodiment, the compounds have the following structure (II):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein:

A is a monocyclic or bicyclic moiety;

B is N or CR′;

L¹ is a bond or NR⁵;

L² is a bond or alkylene;

R′ is H, cyano, alkyl, cycloalkyl, amino, aminylalkyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, aminylalkoxy, alkylaminylalkoxy,alkylaminyl, alkylaminylalkyl, aminylalkylaminyl, carboxyalkyl,alkylcarbonylaminyl, aminylcarbonyl, alkylaminylcarbonyl oraminylcarbonylalkyl;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, halo,hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl (e.g.,CF₃), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈ cycloalkyl,heterocycyclylalkyl, C₁-C₆ alkynyl, C₁-C₆ alkenyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl,aminylcarbonyl; heteroaryl or aryl;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocyclylalkyl; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In some embodiments of structure (II), R^(2a), R^(2b) and R^(2c) areeach independently H, amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆alkyl amino, C₁-C₆ haloalkyl (e.g., CF₃), C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₃-C₈ cycloalkyl, heterocycyclylalkyl, heteroaryl or aryl.In some other embodiments of structure (II), B is N or C—CN. In someembodiments of structure (II), R^(2a), R^(2b) and R^(2c) are eachindependently H, amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ haloalkyl (e.g., CF₃), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocycyclylalkyl, heteroaryl or aryl, and B is N orC—CN.

In some other embodiments, the compound has one of the followingstructures (II′), (II″) or (II′″):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein:

A′ is a monocyclic aryl or heteroaryl;

B is N or CR′;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁵;

L² is a bond or alkylene;

R′ is H, cyano, alkyl, cycloalkyl, amino, aminylalkyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, aminylalkoxy, alkylaminylalkoxy,alkylaminyl, alkylaminylalkyl, aminylalkylaminyl, carboxyalkyl,alkylcarbonylaminyl, aminylcarbonyl, alkylaminylcarbonyl oraminylcarbonylalkyl;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, halo,hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkylaminyl, C₁-C₆ haloalkyl (e.g.,CF₃), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈ cycloalkyl,heterocyclylalkyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl; C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl; C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₃-C₈ cycloalkyl, heterocyclylalkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocycloalkyl;

m¹ and m² are, at each occurrence, independently 1, 2 or 3; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In some embodiments of structures (II′), (II″) or (II′″):

B is N or C—CN; and

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; or R^(3a) and R^(3b) join to form oxo, a carbocyclic orheterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring; and

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; or R^(4a) and R^(4b) join to form oxo, a carbocyclic orheterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring.

In some embodiments, the compound has structure (II′). In otherembodiments of (II′):

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁵;

L² is a bond or alkylene;

R¹ is aryl or heteroaryl;

R^(2a), R^(2b) and R^(2c) are each independently H, amino, halo,hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl (e.g.,CF₃), C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to forma carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(3b) joins with R^(4b) toform a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl, and R^(4b) joins with R^(3b) toform a carbocyclic or heterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocycloalkyl;

m¹ and m² are each independently 1, 2 or 3; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein.

In some different embodiments, A is N. In other embodiments, A is C—CN.

The structure of E is not particularly limited provided it is capable offorming a covalent bond with a nucleophile, such as the cysteine residueat position 12 of a KRAS, HRAS or NRAS G12C mutant protein. Accordingly,moieties which are capable of reaction with (e.g., by covalent bondformation) a nucleophile are preferred. In certain embodiments, E iscapable of reacting in a conjugate addition manner (e.g., 1.4-conjugateaddition) with an appropriately reactive nucleophile. In someembodiments, E comprises conjugated pi bonds such that delocalization ofelectrons results in at least one atom (e.g., a carbon atom) having apositive charge, partial positive charge or a polarized bond. In otherembodiments, E comprises one or more bonds wherein the electronegativityof the two atoms forming the bonds is sufficiently different such that apartial positive charge (e.g., by polarization of the bond) resides onone of the atoms, for example on a carbon atom. E moieties comprisingcarbon-halogen bonds, carbon-oxygen bonds or carbon bonds to variousleaving groups known in the art are examples of such E moieties.

In certain embodiments of the foregoing, E has the following structure:

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR S(═O)₂—;

R⁸ is H, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R⁸ is H, —OH, —CN or C₁-C₆ alkyl; and

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;

when

is a triple bond; then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In certain embodiments when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R⁹ andR¹⁰ join to form a carbocyclic or heterocyclic ring.

In some of the foregoing embodiments, Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂—or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodiments R⁸is H. In other embodiments, R^(8′) is —CN. In other embodiments, R^(8′)is —OH.

Accordingly, in some embodiments, the compound has one of the followingstructures (II′a), (II″a) or (II′″a):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆ alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;and

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆ alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In some embodiments, the compound has structure (II′a).

In other embodiments, the compound has one of the following structures(II′b), (II′c), (II′d), (II′e), (II′f), (II′g), (II″b), (II″c), (II′″b),(II′″c) or (II′″d):

In some embodiments, the compound has one of structures (II′b), (II′c),(II′d) or (II′e).

In any of the foregoing embodiments of the compounds of structure (II),(II′), (II″), (II′″), (II′a), (II″a), (II′″a), (II′b), (II′c), (II′d),(II′e), (II′f), (II′g), (II″b), (II″c), (II′″b), (II′″c) or (II′″d) A isN. In some other of the foregoing embodiments of the compounds ofstructure (II), (II′), (II″), (II′″), (II′a), (II″a), (II′″a), (II′b),(II′c), (II′d), (II′e), (II′f), (II′g), (II″b), (II″c), (II′″b), (II′″c)or (II′″d), A is C—CN.

Without wishing to be bound by theory, Applicants believe correctselection of the R¹ substituent may play a part in the compounds'inhibitory activity (e.g., against KRAS, HRAS or NRAS G12C). In someembodiments, R¹ is aryl or heterocyclyl (e.g., heteroaryl or aliphaticheterocyclyl), each of which is optionally substituted with one or moresubstituents. In some embodiments, R¹ is capable of reversibleinteraction with KRAS, HRAS or NRAS G12C mutant protein. In someembodiments R¹ has high affinity towards KRAS, HRAS or NRAS and ishighly specific towards G12C KRAS, HRAS or NRAS. In some embodiments R¹is capable of hydrophobic interaction with KRAS, HRAS or NRAS G12C. Insome embodiments R¹ is able to form hydrogen bonds with various residuesof G12C KRAS, HRAS or NRAS protein.

In any of the foregoing embodiments, R¹ is aryl. For example in someembodiments R¹ is phenyl, and in other embodiments R¹ is naphthyl. R¹ issubstituted or unsubstituted. In some specific embodiments, R¹ issubstituted with one or more substituents. In some embodiments, R¹ issubstituted with halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆haloalkyl, C₁-C₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl,aryl, heteroaryl, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy orC₁-C₆ alkylcarbonyloxy, or combinations thereof, wherein R is C₁-C₆alkyl. For example, in some embodiments R¹ is substituted with halo,cyano, amino, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,heteroarylalkyloxy or C₁-C₆ alkylcarbonyloxy, or combinations thereof.In some other embodiments R¹ is substituted with halo, hydroxyl, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy or C₁-C₆ alkylcarbonyloxy, orcombinations thereof. In some even more embodiments, R¹ is substitutedwith fluoro or hydroxyl, or combinations thereof.

In some more specific embodiments, R¹ has one of the followingstructures:

In some more specific embodiments, R¹ has one of the followingstructures:

In some more specific embodiments, R¹ has one of the followingstructures:

In some other embodiments, R¹ has one of the following structures:

In still different embodiments, R¹ has one of the following structures:

In some different embodiments of the foregoing compounds, R¹ isheteroaryl, for example a heteroaryl comprising nitrogen. In otherembodiments, R¹ is indazolyl or quinolinyl. In more embodiments, R¹ isheteroaryl which is substituted with one or more substituents. Forexample, in certain embodiments, R¹ is substituted with hydroxyl, haloor C₁-C₆ alkyl, or both, for example hydroxyl or C₁-C₆ alkyl, or both.

In some embodiments, R^(2a), R^(2b) and/or R^(2c) are CF₃. In some ofthe foregoing embodiments R^(2c) is H. In other of any of the foregoingembodiments, R^(2a) and R^(2b) are each halo. For example, in someembodiments R^(2a) is fluoro, and in other embodiments, R^(2b) ischloro. In different embodiments R^(2a) is fluoro, and R^(2b) is chloro.

In some more specific embodiments, the compounds have the followingstructure (II′f):

For example, in even further different embodiments, the compounds haveone of the following structures (II′g) or (II′h):

In some further embodiments, A is mono-cyclic heterocycle (e.g., a7-membered mon-cyclic heterocycle), fused-bicyclic heterocycle, aspiro-bicyclic heterocycle, heteroaryl or aryl. For example, in someembodiments A is phenyl, pyridinyl, thiazolyl, oxazolyl, imidazolyl,pyrrolyl, pyrazolyl, diazapanyl, 2,6-diazaspiro[3.3]heptanyl,2,6-diazaspiro[3.4]octanyl, piperazinyl oroctahydropyrrolo[3,4-c]pyrrole. In more specific embodiments, A has oneof the following structures:

In some specific embodiments, A has the following structure:

In some specific embodiments, A has the following structure:

In yet more of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl; and

R⁹ and R¹⁰ are each independently H, halo, cyano, carboxyl, C₁-C₆ alkyl,alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl,heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R⁹ and R¹⁰ join toform a carbocyclic, heterocyclic or heteroaryl ring.

In still other of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl; and

R¹⁰ is H, C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

The Q moiety is typically selected to optimize the reactivity (i.e.,electrophilicity) of E. In some of the foregoing embodiments Q is—C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—. In certain of theforegoing embodiments, Q is —C(═O)—. In other embodiments, Q is—S(═O)₂—. In still more embodiments, Q is —NR⁸C(═O)—. In still moredifferent embodiments, Q is —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodimentsR^(8′) is H. In other embodiments, R^(8′) is —CN. In other embodiments,R^(8′) is —OH.

In some of the foregoing embodiments, R⁸ is H. In other of theseembodiments, R⁸ is hydroxylalkyl, for example in some embodiments thehydroxylalkyl is 2-hydroxylalkyl.

In some of any one of the foregoing embodiments, at least one of R⁹ orR¹⁰ is H. For example, in some embodiments each of R⁹ and R¹⁰ are H.

In other of the foregoing embodiments, R¹⁰ is alkylaminylalkyl. In someof these embodiments, R¹⁰ has the following structure:

In other embodiments, R¹⁰ is hydroxylalkyl, such as 2-hydroxylalkyl.

In some other different embodiments of the foregoing embodiments, R⁹ andR¹⁰ join to form a carbocyclic ring. For example, in some of theseembodiments the carbocyclic ring is a cyclopentene, cyclohexene orphenyl ring. In other embodiments, the carbocyclic ring is acyclopentene or cyclohexene ring. In other embodiments, the carbocyclicring is a phenyl ring, for example a phenyl ring having the followingstructure:

In some of any of the foregoing embodiments E is an electrophile capableof bonding with a KRAS, HRAS or NRAS protein comprising G12C mutation.In some embodiments, the electrophile E is capable of forming anirreversible covalent bond with a G12C mutant KRAS, HRAS or NRASprotein. In some cases, the electrophile E may bind with the cysteineresidue at the position 12 of a G12C mutant KRAS, HRAS or NRAS protein.In various embodiments of any of the foregoing, E has one of thefollowing structures:

In some embodiments, E has one of the following structures:

In other embodiments of any of the foregoing, E has one of the followingstructures:

In different embodiments, E has one of the following structures:

In some embodiments, E has the following structure:

In other embodiments, E has the following structure:

In some cases E has one of the following structures:

wherein:

R⁸ is H or C₁-C₆alkyl;

R⁹ is H, cyano or C₁-C₆alkyl, or R⁹ joins with R¹⁰ to form a carbocycle;

R¹⁰ is H or C₁-C₆alkyl or R¹⁰ joins with R⁹ to form a carbocycle and

R^(10a) is H or C₁-C₆alkyl.

In some embodiments E is

In some embodiments E is

In some embodiments E is

In some of any of the foregoing embodiments, L¹ is a bond. In otherembodiments, L¹ is NR⁵. For example, in some of these embodiments, R⁵ isC₁-C₆alkyl. In other embodiments, L¹ is NH.

L² can be selected to provide proper spacing and/or orientation for theE group to form a bond with the KRAS, HRAS or NRAS protein. In some ofthe foregoing embodiments, L² is a bond. In other of the foregoingembodiments, L² is alkylene. In some embodiments, the alkylene issubstituted. In other embodiments the alkylene is unsubstituted. Forexample, in some embodiments L² is CH₂ or CH₂CH₂.

In certain embodiments, R^(3a) and R^(3b) are, at each occurrence,independently H, —OH, —NH₂, —CO₂H, halo, cyano, hydroxylalkly,aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl, and R^(4a) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H, —OH, hydroxylalkly, cyano, oraminylcarbonyl and R^(3b) and R^(4b) are H.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H or C₁-C₆ alkyl. In some embodiments, atleast one of R^(3a), R^(4a), R^(3b) and R^(4b) is independently C₁-C₆alkyl, such as methyl. In some embodiments, one occurrence of R^(3a) isC₁-C₆ alkyl, such as methyl, and the remaining R^(3a) and each R^(4a) isH. In some other embodiments, two occurrences of R^(3a) are C₁-C₆ alkyl,such as methyl, and the remaining R^(3a) and each R^(4a) is H. In someother embodiments, one occurrence of R^(3a) and one occurrence of R^(4a)is independently C₁-C₆ alkyl, such as methyl, and the remaining R^(3a)and R^(4a) are each H.

In certain other embodiments, R^(3a) and R^(4a) are H and R^(3b) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In any of the foregoing embodiments, at least one of R^(3a), R^(3b),R^(4a) or R^(4b) is H. In some embodiments, each of R^(3a), R^(3b),R^(4a) and R^(4b) are H.

In some embodiments, R^(3a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b), R^(4a) and R^(4b) are H.

In other embodiments, R^(4a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3a), R^(3b) and R^(4b) are H.

In other embodiments, R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b) joins with R^(4b) to form a carbocyclic or heterocyclic ring;

In still more embodiments, R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(4b) joins with R^(3b) to form a carbocyclic or heterocyclic ring.

In other embodiments, R^(3a) and R^(3b) join to form a carbocyclic orheterocyclic ring. In other embodiments, R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring.

In still other embodiments, R^(3a) or R^(4a) is aminylcarbonyl. Forexample, in certain embodiments, the aminylcarbonyl is

In other embodiments, R^(3a) or R^(4a) is cyano. In other embodiments,R^(3a) or R^(4a) is —OH. In other embodiments, R^(3a) or R^(4a) ishydroxylalkyl, for example hydroxylmethyl.

In some embodiments of any of the foregoing compounds (e.g., thecompounds of structures (II), (II′a), (II′b), (II′c), (II′d) or (II′e)),R¹ is aryl or heteroaryl and R^(2a), R^(2b) and R^(2c) are independentlyselected from H and halo, for example in some further embodiments R¹ isaryl or heteroaryl and R^(2a) and R^(2b) are independently selected fromhalo, such as chloro and fluoro, and R^(2c) is H. In some embodiments,R¹ is aryl or heteroaryl, R^(2a) is chloro, R^(2b) is fluoro and R^(2c)is H. In other embodiments R¹ is aryl or heteroaryl, one of R^(2a) orR^(2b) is halo, such as chloro or fluoro, and the other one of R^(2a) orR^(2b) is H.

In some embodiments of any of the compounds described herein, C₁-C₆haloalkyl is CF₃ (e.g., when one or more of R^(2a), R^(2b) or R^(2c) isC₁-C₆ haloalkyl).

In some embodiments m¹ is 1. In other embodiments m¹ is 2. In still moreembodiments, m¹ is 3. In different embodiments, m² is 1. In some otherembodiments, m² is 2. In yet still more embodiments, m² is 3.

In some other particular embodiments of any of the foregoing compounds,m¹ is 1, and m² is 1. In other embodiments, m¹ is 1 and, m² is 2. Instill other embodiments m¹ is 2, and m² is 2. In more embodiments, m¹ is1, and m² is 3.

In any of the foregoing embodiments, G¹ and G² are each independentlyselected from N and CH. In some embodiments, at least one of G¹ or G² isN. In some embodiments, each of G¹ and G² are N. In some embodiments,each of G¹ and G² are N and m¹ and m² are each 2. In some otherembodiments, at least one of G¹ or G² is CH. In other embodiments, eachof G¹ and G² are CH.

For example, in other embodiments the compounds have one of thefollowing structures (II′i) or (II′j):

wherein R¹, R^(2a), R^(2b) and R^(2c) are as defined according to any ofthe foregoing embodiments.

In any of the foregoing embodiments, A is N. In other of the foregoingembodiments, A is C—CN.

Some embodiments of the compounds include more than one stereoisomer.Other embodiments are directed to a single stereoisomer. In someembodiments the compounds are racemic (e.g., mixture of atropisomers),while in other embodiments the compounds are substantially a singleisomer, for example a substantially purified atropisomer.

In various different embodiments, the compound of structure (II) has oneof the structures set forth in Table 3 below. The compounds in Table 3were each prepared and analyzed by mass spectrometry and/or ¹H NMR.Experimental mass spectrometry data is included in Table 3. Exemplarysynthetic procedures are described in more detail below and in theExamples. General methods by which the compounds may be prepared areprovided below and indicated in Table 3.

TABLE 3 Representative Compounds of Structure (II) No. Structure NameMethod [M + H]⁺ II-1

(E)-1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl)piperazin- 1-yl)-4- morpholinobut-2-en- 1-one R 530.2  II-2

(E)-4-(azetidin-1-yl)- 1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6-hydroxyphenyl) quinazolin-4- yl)piperazin- 1-yl)but-2-en-1-one R 500.2 II-3

1-(4-(6-chloro-7-(2,3- difluoro-6- hydroxyphenyl)-8- fluoroquinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 449.1  II-4

1-(6-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)-2,6- diazaspiro[3.4]octan- 2-yl)prop-2-en-1-one S457.15 II-5

1-(4-(6-chloro-7-(2- (difluoromethyl)-6- fluorophenyl) quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 447.10 II-6

1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- ((1-methyl-1H- imidazol-5-yl)methoxy)phenyl) quinazolin-4- yl)piperazin-1- yl)prop-2-en-1-one R525.30 II-7

1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)-1,4- diazepan-1-yl)prop-2- en-1-one S 445.15 II-8

1-(2-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)-2,6- diazaspiro[3.4]octan- 6-yl)prop-2-en-1-one S457.10 II-9

1-(3-((6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl)amino)pyrrolidin- 1-yl)prop-2-en-1-one S 431.10 II-10

1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- ((1-methyl-2-nitro-1H-imidazol-5- yl)methoxy)phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one S 570.15 II-11

N-(3-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl) quinazolin-4-yl)phenyl)acrylamide T 438.15 II-12

N-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)pyridin- 2-yl)acrylamide T 439.10 II-13

N-(5-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)thiazol- 2-yl)acrylamide T 445.00 II-14

(S)-2-(4-(4- acryloylpiperazin-1- yl)-6-chloro-8- fluoroquinazolin-7-yl)-3-fluorophenyl dihydrogen phosphate R 511.0  II-15

(S)-(2-(4-(4- acryloylpiperazin-1- yl)-6-chloro-8- fluoroquinazolin-7-yl)-3-fluoro- phenoxy)methyl- phosphonic acid R 541.1* *M + Na⁺

In various different embodiments of any of the embodiments of thecompounds of structure (II), the compounds illustrated in Table 4 areexcluded from the invention.

TABLE 4 Compounds Excluded From Certain Embodiments No. Structure Name2-1

1-(4-(6- chloro-7- phenyl- quinazolin-4- yl)piperazin- 1-yl)prop-2-en-1-one 2-2

1-(4-(6- chloro-7-(2- chlorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-3

1-(4-(6- chloro-7-(3- chlorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-4

1-(4-(6- chloro-7-(2- hydroxy- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-5

1-(4-(6- chloro-7-(3- hydroxy- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-6

1-(4-(6- chloro-7-(2- ethylphenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-7

1-(4-(6- chloro-7-(4- chlorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-8

1-(4-(6- chloro-7-(3- ethylphenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-9

1-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-10

(E)-1-(4-(6- chloro-7- phenyl- quinazolin-4- yl)piperazin- 1-yl)-4-(dimethyl- amino)but- 2-en-1-one 2-11

1-(4-(6- chloro-7-(4- fluorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-12

1-(4-(6- chloro-7-(3- fluorophenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-13

2-(1- acryloyl-4- (6-chloro-7- phenyl- quinazolin-4- yl)piperazin- 2-yl)acetonitrile 2-14

1-(4-(6- cyclopropyl- 7-phenyl- quinazolin-4- yl)piperazin- 1-yl)prop-2-en-1-one 2-15

1-(4-(7- phenyl- quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-16

N-(1-(6- chloro-7- phenyl- quinazolin-4- yl)piperidin- 4- yl)acrylamide2-17

1-(4-(6- chloro-7- (pyridin-3-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-18

1-(4-(6- chloro-7- (pyridin-2-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-19

1-(4-(6- ethyl-7- phenyl- quinazolin-4- yl)piperazin- 1-yl)prop-2-en-1-one 2-20

1-(3-(6- chloro-7- phenyl- quinazolin-4- ylamino) azetidin-1- yl)prop-2-en-1-one 2-21

1-(4-(6- chloro-7-(2- methoxy- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-22

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)benzamide 2-23

1-(4-(6- chloro-7-(2- isopropyl- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-24

1-(4-(6- chloro-7-(2- (trifluoro- methyl) phenyl) quinazolin- 4-yl)piperazin- 1-yl)prop-2- en-1-one 2-25

1-(4-(6- chloro-7- (2,5-dichloro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-26

1-(4-(6- chloro-7- (2,4-dichloro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-27

1-(4-(6- chloro-7-(2- (methoxy- methyl) phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-28

1-acryloyl-4- (6-chloro-7- phenyl- quinazolin-4- yl)piperazine- 2-carboxamide 2-29

2-(4-(4- acryloyl- piperazin- 1-yl)-6- chloro- quinazolin- 7-yl)benzonitrile 2-30

2-(1- acryloyl-4- (6-chloro-7- (2- fluorophenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-31

2-(1- acryloyl-4- (6-chloro-7- (2- ethylphenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-32

1-(4-(6- chloro-7-(2- (hydroxy- methyl) phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-33

2-(1- acryloyl-4- (6-chloro-7- (2- chlorophenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-34

2-(1- acryloyl-4- (6-chloro-7- (4- chlorophenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-35

2-(1- acryloyl-4- (6-chloro-7- (4- chlorophenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-36

1-(4-(6- chloro-7- (2,4-difluoro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-37

1-(4-(6- chloro-7- (2,5- difluoro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-38

1-(4-(6- chloro-7-(4- chloro-2- fluorophenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-39

1-(4-(6- chloro-7-(5- chloro-2- fluorophenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-40

1-(4-(6- chloro-7- phenyl- quinazolin- 4-yl)-2- (hydroxy- methyl)piperazin- 1-yl)prop- 2-en-1-one 2-41

1-(4-(6- chloro-7-(4- chloro-2- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-42

1-(4-(6- chloro-7-(5- chloro-2- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-43

1-(4-(6- chloro-7-(4- fluoro-2- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-44

1-acryloyl-4- (6-chloro-7- (2- fluorophenyl) quinazolin-4-yl)piperazine- 2- carboxamide 2-45

l-acryloyl-4- (6-chloro-7- (2-(trifluoro- methyl) phenyl) quinazolin-4-yl)piperazine- 2- carboxamide 2-46

1-(4-(6- chloro-7-(5- fluoro-2- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-47

1-(4-(6- chloro-7- (naphthalen- 1-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-48

1-(4-(6- chloro-7-(2- (trifluoro- methyl) phenyl) quinazolin-4-yl)-2-methyl- piperazin-1- yl)prop-2- en-1-one 2-49

2-(1- acryloyl-4- (6-chloro-7- (2-(trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 2-yl) acetonitrile 2-50

1-(4-(6- chloro-7-(2- cyclopropyl- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-51

1-(4-(6- chloro-7-(2- chloro-5- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-52

1-(4-(7- (benzo[d] oxazol-7- yl)-6-chloro- quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-53

3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)benzonitrile 2-54

3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)-2-fluoro-N,N- dimethyl- benzamide 2-55

1-(4-(6- chloro-7- (2,6-difluoro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-56

1-(4-(6- chloro-7-(4- fluoro-2- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-57

l-(4-(6- chloro-7-(2- hydroxy- phenyl) quinazolin-4- yl)-2-methyl-piperazin-1- yl)prop-2- en-1-one 2-58

1-(4-(6- chloro-7- (quinolin- 5-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-59

1-(4-(6- chloro-7- (isoquinolin- 5-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-60

4-(4-acryloyl- piperazin-1- yl)-7-(2- fluorophenyl) quinazoline-6-carbonitrile 2-61

1-(4-(6- chloro-7-(2- fluoro-6- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-62

2-(1- acryloyl-4- (6-chloro-7- (2,4-difluoro- phenyl) quinazolin-4-yl)piperazin- 2-yl) acetonitrile 2-63

1-(4-(6- chloro-7-(5- methyl-1H- indazol- 4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-64

1-(4-(6- chloro-7-(2- fluoro-5- (trifluoro- methoxy) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-65

3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)-N-cyclopropyl- benzamide 2-66

1-(3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)-4-fluorophenyl) cyclopropane- carbonitrile 2-67

1-(4-(6- chloro-7- (1H-indazol- 5-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-68

1-acryloyl-4- (6-chloro-7- (2,4-difluoro- phenyl) quinazolin-4-yl)piperazine- 2-carbonitrile 2-69

1-acryloyl-4- (6-chloro-7- (2-hydroxy- phenyl) quinazolin-4-yl)piperazine- 2-carbonitrile 2-70

1-(4-(6- chloro-7-(5- cyclopropyl- 2-fluoro- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-71

1-(4-(6- chloro-7- (5,6,7,8- tetrahydro- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-72

1-(4-(7-(3- amino- benzo[d] isoxazol- 4-yl)-6- chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-73

1-(4-(7-(2- fluorophenyl)- 6-(trifluoro- methyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-74

1-(4-(6- chloro-7- (1H-indazol- 7-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-75

1-(4-(6- chloro-7-(2- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-76

1-(4-(6- chloro-7-(2- ethynyl- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-77

3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-4-fluoro- benzamide 2-78

1-(4-(6- chloro-7-(2- (cyclopropyl- methyl) phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-79

1-(4-(7-(2- (trifluoro- methyl) phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-80

1-(4-(6- chloro-8- fluoro-7-(2- fluorophenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-81

4-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)indolin-2- one 2-82

2-(2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)phenyl) acetamide 2-83

1-(4-(6- chloro-7-(1H- indazol-6- yl)quinazolin- 4- yl)piperazin-1-yl)prop-2- en-1-one 2-84

1-(4-(7-(2- fluorophenyl)- 6-hydroxy- quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-85

1-(4-(7-(2- aminobenzo [d]oxazol-5- yl)-6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-86

1-(4-(7-(1H- benzo[d] imidazol-4- yl)-6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-87

1-(4-(6- chloro-7- (1H-indazol- 4-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-88

2-(2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)phenyl) acetonitrile 2-89

1-(4-(6- chloro-7-(4- hydroxy-2- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-90

3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7- yl)pyridin-2(1H)-one 2-91

N-(3-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7- yl)-4-fluorophenyl) acetamide 2-92

1-(2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)phenyl) cyclopropane- carbonitrile 2-93

1-(2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)phenyl) cyclopropane- carboxamide 2-94

1-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-5-chloro- pyridin- 2(1H)-one 2-95

N-(4-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-5-methyl- pyrimidin-2- yl)acrylamide 2-96

1-(4-(7-(2- amino-5- methyl- pyrimidin-4- yl)-6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-97

1-(4-(6- chloro-7,8′- biquinazolin- 4-yl) piperazin-1- yl)prop-2-en-1-one 2-98

1-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-4-chloro- pyridin- 2(1H)-one 2-99

1-(4-(7-(2- (1H-pyrazol- 4-yl)phenyl)- 6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-100

1-(4-(6- chloro-7- (thiophen- 2-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-101

1-(4-(6- chloro-7-(2- (thiazol-2- yl)phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-102

1-(4-(6- chloro-7-(2- (thiazol-5- yl)phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-103

1-(4-(6- chloro-7-(2- fluoro-5- (1H-pyrazol- 4- yl)phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-104

1-(4-(7-(2- amino-4- methyl- pyrimidin-5- yl)-6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-105

1-(4-(6- chloro-7-(2- methyl-5- (methyl- amino) phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-106

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-3-fluoro- benzonitrile 2-107

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-5-fluoro- benzamide 2-108

1-(4-(6- chloro-7-(2- fluoro-6- methoxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-109

1-(4-(6- chloro-7- (2,4-difluoro- phenyl) quinazolin-4- yl)-2-ethynyl-piperazin-1- yl)prop-2- en-1-one 2-110

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-4-fluoro- benzamide 2-111

1-(4-(7- (benzo[b] thiophen-3- yl)-6-chloro- quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-112

1-(4-(6- chloro-7-(2,3- difluoro-6- methoxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-113

1-(4-(6- chloro-7- (2,2-difluoro- benzo[d] [1,3]dioxol- 4-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-114

1-(4-(6- chloro-7- (2,3-dihydro- benzo[b] [1,4]dioxin- 5-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-115

1-(4-(6- chloro-7-(2- methoxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-116

1-(4-(6- chloro-7- (2,3-difluoro- 6-hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-117

1-(4-(7-(2,4- difluoro- phenyl)-6- (trifluoro- methyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-118

5-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)-3,4-dihydro- quinolin- 2(1H)-one 2-119

1-(4-(6- chloro-7- (2,4- difluoro-5- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-120

1-(4-(7-(2- chloro-5- hydroxy- phenyl)-6- (trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-121

1-(4-(7-(2- fluoro-6- hydroxy- phenyl)-6- (trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-122

1-(4-(6- chloro-8- fluoro-7-(2- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-123

1-(4-(6,8- dichloro-7- (2-fluoro- phenyl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-124

2-(4-(4- acryloyl- piperazin-1- yl)-6- (trifluoro- methyl) quinazolin-7-yl)benzamide 2-125

1-(4-(6- (trifluoro- methyl)-7- (2-(trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-126

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7- yl)benzene-sulfonamide 2-127

1-(4-(6- chloro-7- (quinolin- 4-yl) quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one 2-128

1-(4-(6- chloro-7- (3,6-difluoro- 2-hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-129

1-(4-(6- chloro-7-(2- chloro-5- hydroxy- phenyl)-8- fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-130

1-(4-(7-(2- hydroxy- naphthalen- 1-yl)-6- (trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-131

(E)-1-(4-(6- chloro-7- (2,4-difluoro- phenyl) quinazolin-4-yl)piperazin- 1-yl)-4- (dimethyl- amino)but-2- en-1-one 2-132

1-(4-(6- chloro-7-(2- (1-methyl- cyclopropyl) phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-133

1-(4-(6- chloro-7- (1,2,3,4- tetrahydro- quinolin- 5-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-134

1-(4-(6- chloro-7- (2,4-difluoro- phenyl)-8- fluoro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-135

1-(4-(6- chloro-7-(1- methyl-1H- indazol-3-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-136

1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-137

(E)-1-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazin-1-yl)-4- (dimethyl- amino)but-2- en-1-one 2-138

(E)-1-(4-(6- chloro-8- fluoro-7-(2- fluorophenyl) quinazolin-4-yl)piperazin- 1-yl)-4- (dimethyl- amino)but-2- en-1-one 2-139

(E)-4- (dimethyl- amino)-1- (4-(8-fluoro- 6,7-bis(2- fluorophenyl)quinazolin-4- yl)piperazin- 1-yl)but-2- en-1-one 2-140

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7-yl)-3-fluoro- benzamide 2-141

1-(4-(6- chloro-7-(2- hydroxy-6- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-142

1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-143

1-(4-(6- chloro-8- fluoro-7-(2- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-144

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- 8-fluoro- quinazolin-7-yl)benzamide 2-145

1-(4-(7-(5- methyl-1H- indazol-4-yl)- 6-(trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-146

(E)-ethyl 4- (4-(6-chloro- 7-(2,4- difluoro- phenyl) quinazolin-4-yl)piperazin- 1-yl)-4- oxobut-2- enoate 2-147

8-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin-7- yl)quinolin-2(1H)-one 2-148

(E)-2-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazine-1-carbonyl)- 4-methyl- pent-2- enenitrile 2-149

2-(1- acryloyl-4- (6-chloro-8- fluoro-7-(2- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 2-yl) acetonitrile 2-150

1-(4-(6- chloro-7-(5- methoxy- 1H-indazol- 4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-151

(E)-2-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazine-1-carbonyl)- 3-(thiazol- 5-yl) acrylonitrile 2-152

1-(4-(6- chloro-7- (2,4-difluoro- phenyl) quinazolin-4- yl)piperazin-1-yl)-4- hydroxybut- 2-yn-1-one 2-153

1-(4-(6- chloro-7-(3- methoxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-154

1-(4-(6- chloro-7-(2- hydroxy- 5,6,7,8- tetrahydro- naphthalen- 1-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-155

1-(4-(6- chloro-7-(3- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-156

1-(4-(6- chloro-8- fluoro-7-(2- fluorophenyl) quinazolin- 4-yl)-2-ethynyl- piperazin-1- yl)prop-2- en-1-one 2-157

1-(4-(6- chloro-7- (5,6- dimethyl-1H- indazol-7-yl)- 8-fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-158

1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)-2- (hydroxy- methyl) piperazin-1- yl)prop- 2-en-1-one 2-159

(E)-2-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazine-1-carbonyl)- 3-(4-methyl- oxazo1-2-yl) acrylonitrile 2-160

(E)-2-(4-(6- chloro-7-(2- fluorophenyl) quinazolin-4- yl)piperazine-1-carbonyl)-5- hydroxy-4,4- dimethyl- pent-2- enenitrile 2-161

1-(4-(6- chloro-7-(6- methyl-1H- indazol-4- yl)quinazolin- 4-yl)piperazin-1- yl)prop-2- en-1-one 2-162

(Z)-4-(4-(6- chloro-7- (2,4- difluoro- phenyl) quinazolin-4-yl)piperazin- 1-yl)-4- oxobut-2- enenitrile 2-163

1-(4-(6- chloro-7-(5- chloro-1H- indazol-7- yl)quinazolin- 4-yl)piperazin-1- yl)prop-2- en-1-one 2-164

2-(4-(4- acryloyl- piperazin-1- yl)-6-chloro- quinazolin- 7-yl)-3-hydroxy- benzonitrile 2-165

1-(4-(6- chloro-7-(6- chloro-1H- indazol-4- yl)quinazolin- 4-yl)piperazin-1- yl)prop-2- en-1-one 2-166

1-(4-(6- chloro-7-(2- fluoro-5-(2- hydroxy- propan-2- yl)phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-167

1-(4-(6- chloro-7-(6- methyl-1H- indazol-7- yl)quinazolin- 4-yl)piperazin-1- yl)prop-2- en-1-one 2-168

1-(4-(8- fluoro-7-(2- fluorophenyl)- 6-(trifluoro- methyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-169

1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-170

1-(4-(8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)-6- (trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-171

1-(4-(6- chloro-8- fluoro-7-(6- methyl-1H- indazol-7-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-172

1-(4-(6- chloro-8- fluoro-7-(4- fluoro-2- (trifluoro- methyl) phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-173

1-(4-(7-(3- (1H-pyrazol- 5-yl)phenyl)- 6-chloro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-174

1-(4-(6- chloro-7- (3,6- difluoro-2- hydroxy- phenyl)-8- fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-175

1-(4-(6- chloro-8- fluoro-7-(2- (2-hydroxy- propan-2- yl)phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-176

1-(4-(6- chloro-7- (2,4- difluoro-6- hydroxy- phenyl)-8- fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-177

1-(4-(6- chloro-8- fluoro-7-(2- fluoro-5- (1H- imidazol-4- yl)phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-178

(E)-2-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazine- 1-carbonyl)-4- methylpent- 2-enenitrile2-179

(E)-2-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazine- 1-carbonyl)- 3-(thiazol- 5-yl)acrylonitrile 2-180

(E)-2-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazine- 1-carbonyl)- 3-(pyridin- 2-yl)acrylonitrile 2-181

1-(4-(6,8- dichloro-7- (2-methoxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-182

1-(4-(6- chloro-8- fluoro-7-(2- methoxy-6- methylphenyl) quinazolin-4-yl) piperazin-1- yl)prop-2- en-1-one 2-183

1-(4-(6- chloro-8- fluoro-7- (1H-indol-3- yl)quinazolin- 4-yl)piperazin-1- yl)prop-2- en-1-one 2-184

1-(4-(6- chloro-7-(2- chloro-6- hydroxy- phenyl)-8- fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-185

1-(4-(6- chloro-7-(2- chloro-6- methyl- phenyl)-8- fluoro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-186

1-(4-(7-(2,4- difluoro- phenyl)-8- fluoro-6- methyl- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-187

2-(1- acryloyl-4- (6-chloro-8- fluoro-7-(5- methyl-1H- indazol- 4-yl)quinazolin-4- yl)piperazin- 2-yl) acetonitrile 2-188

(E)-1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol-4- yl)quinazolin-4-yl) piperazin-1- yl)-4- (dimethyl- amino)but-2- en-1-one 2-189

1-(4-(7-(2,4- difluoro- phenyl)-6,8- difluoro- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-190

1-(4-(6,8- difluoro-7- (5-methyl- 1H-indazol- 4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-191

1-(4-(6,8- difluoro-7- (6-methyl- 1H-indazol- 7-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-192

1-(4-(6,8- difluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-193

(E)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazin- 1-yl)-4- (dimethyl- amino)but-2- en-1-one2-194

1-(4-(6- chloro-8- methoxy-7- (5-methyl- 1H-indazol- 4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-195

1-(4-(6,8- dichloro-7- (2-hydroxy- naphthalen- 1-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-196

1-(4-(6- chloro-7- (2,4-difluoro- phenyl)-8- methoxy- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-197

1-(4-(6- chloro-7-(5- (difluoro- methyl)-2- fluorophenyl)- 8-fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-198

(E)-4-amino- 1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol- 4-yl)quinazolin-4- yl)piperazin- 1-yl)but-2- en-1-one 2-199

1-(4-(6- chloro-7-(2- fluoro-6- hydroxy- phenyl)-8- methoxy-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-200

(E)-1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol- 4-yl)quinazolin-4- yl)piperazin- 1-yl)-4- hydroxybut- 2-en-1-one 2-201

1-(4-(6- chloro-7-(2- fluoro-6- hydroxy- phenyl)-5- (trifluoro- methyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-202

1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol-4- yl)quinazo-lin-4-yl)-2- (hydroxy- methyl) piperazin-2- yl)prop- 2-en-1-one 2-203

1-(4-(6- chloro-7- (2,4-difluoro- phenyl)-8- hydroxy- quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-204

1-(4-(6- chloro-8- fluoro-7-(3- methyl-1H- indazol- 7-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-205

(E)-1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)quinazolin-4- yl)piperazin- 1-yl)-4- (dimethyl- amino)but-2- en-1-one2-206

1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol- 4-yl) quinazolin-4-yl)-2-methyl- piperazin-1- yl)prop-2- en-1-one 2-207

(E)-1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)quinazolin-4- yl)piperazin- 1-yl)but-2- en-1-one 2-208

1-(4-(6- chloro-8- fluoro-7-(5- fluoro-1H- indazol- 4-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-209

(R)-1-(4-(6- chloro-8- fluoro-7-(5- methyl-1H- indazol- 4-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-210

(E)-4-amino- 1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl)quinazolin-4- yl)piperazin- 1-yl)but-2- en-1-one 2-211

1-(4-(6- chloro-7-(3- (difluoro- methyl) naphthalen- 1-yl)-8-fluoro-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-212

1-(4-(6- chloro-8- fluoro-7-(3- fluoro-5- methyl-1H- indazol- 4-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-213

1-(4-(6- chloro-5- fluoro-7-(2- fluoro-6- hydroxy- phenyl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-214

1-(4-(6- chloro-8- fluoro-7-(3- hydroxy- naphthalen- 1-yl) quinazolin-4-yl)-2- ((dimethyl- amino) methyl) piperazin-1- yl)prop-2- en-1-one 2-215

1-(4-(6- chloro-7-(3- hydroxy- naphthalen- 1-yl)-8- methoxy-quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-216

(S)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-217

1-(4-(6- chloro-8- fluoro-7-(6- fluoro-3- methyl-1H- indazol- 7-yl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-218

1-(4-(6- chloro-7-(2- ((dimethyl- amino) methyl)-6- fluorophenyl)-8-fluoro- quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one 2-219

1-(4-(6- chloro-8- fluoro-7-(6- fluoro-1H- indazol- 7-yl) quinazolin-4-yl)piperazin- 1-yl)prop-2- en-1-one 2-220

(R)-1-(4-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin-4- yl)piperazin- 1-yl)prop-2- en-1-one

The following General Reaction Schemes illustrate exemplary methods ofmaking compounds of compounds of structure (II):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein R¹, R^(2a), R^(2b), R^(2c), L¹, L², A, B and E are as definedherein. It is understood that one skilled in the art may be able to makethese compounds by similar methods or by combining other methods knownto one skilled in the art. It is also understood that one skilled in theart would be able to make, in a similar manner as described below, othercompounds of structure (II) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention.

Embodiments of the compound of structure (II) (e.g., compound R-11) canbe prepared according to General Reaction Scheme 18 (“Method R”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 18, compounds of structure R-1 are purchased fromcommercial sources and reduced under appropriate conditions to formaniline R-2. R-2 is then treated with 2,2,2-trichloroethane-1,1-diol andsodium sulfate to yield R-3, which is subsequently cyclized by treatmentwith concentrated sulfuric acid. Ring-opening oxidation of R-4 thenyields R-5, which can be optionally chlorinated to yield R-6 when achloro substituent in the R^(2b) position is desired. Cyclization of R-6provides R-7, which is then treated with thionyl chloride to provideR-8. Compound R-8 is then reacted with mono-boc piperazine to provideR-9. The desired R¹ moiety is installed via Suzuki chemistry to provideR-10. Deprotection of R-10, followed by reaction with an appropriateacrylic acid under amide coupling conditions then yields R-11.

Embodiments of the compound of structure (I) (e.g., compound S-8) can beprepared according to General Reaction Scheme 19 (“Method S”), whereinR¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 19, compounds of structure S-1 are purchased fromcommercial sources and treated under Suzuki conditions to yield S-2.Chlorination of S-2 with N-chlorosuccinimide yields S-3, which iscyclized to quinazolinol S-4. Chlorination of S-4 and reaction with anappropriate heterocycle (e.g., monocyclic or spirocyclic as representedby S-6) or substituted amine (not illustrated) yields S-7. Treatment ofS-7 according to the general procedures described above yields S-8.

Embodiments of the compound of structure (I) (e.g., compound T-4) can beprepared according to General Reaction Scheme 20 (“Method T”), whereinA′, R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 20, compounds of structure S-5 are prepared according toGeneral Reaction Scheme 2. Suzuki coupling of B-5 with T-1 yields T-2,which can be reduced to amine T-3. Acylation of T-3 under appropriateconditions yields T-4.

Compounds of Structure (III)

In yet other embodiments, the compounds have the following structure(III):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein:

A is N or CH:

B is N or CR′;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁵;

L² is a bond or alkylene;

R′ is H, cyano, alkyl, cycloalkyl, amino, aminylalkyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, aminylalkoxy, alkylaminylalkoxy,alkylaminyl, alkylaminylalkyl, aminylalkylaminyl, carboxyalkyl,alkylcarbonylaminyl, aminylcarbonyl, alkylaminylcarbonyl oraminylcarbonylalkyl;

R¹ is aryl or heteroaryl;

R^(2a) and R^(2b) are each independently amino, halo, hydroxyl, cyano,C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₃-C₈ cycloalkyl, heterocycyclylalkyl, C₁-C₆ alkynyl, C₁-C₆alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;

R^(2c) is H, amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈cycloalkyl, heterocycyclylalkyl, C₁-C₆ alkynyl, C₁-C₆ alkenyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈cycloalkyl, heterocyclylalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(3b) joins with R^(4b) to form a carbocyclic orheterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈cycloalkyl, heterocyclylalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(4b) joins with R^(3b) to form a carbocyclic orheterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocyclylalkyl;

x and y are independently integers ranging from 0 to 2; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein each occurrence of alkylene, aryl, heteroaryl, cycloalkyl,heterocyclyl, alkylaminyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy,cycloalkyl, hereocyclylalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl, and carbocyclic and heterocyclic rings isoptionally substituted with one or more substituents unless otherwisespecified; and

provided that at least one occurrence of R^(3a), R^(3b), R^(4a) orR^(4b) is not H, and provided that when R¹ is indazolyl or naphthyl andone of R^(3a) or R^(3b) is methyl, dimethylaminomethyl orhydroxylmethyl, then at least one additional occurrence of R^(3a) orR^(3b) or at least one occurrence of R^(4a) or R^(4b) is not H.

In different embodiments of compounds of structure (III):

A is N or CH:

B is N, CH or C—CN;

G¹ and G² are each independently N or CH;

L¹ is a bond or NR⁵;

L² is a bond or alkylene;

R¹ is aryl or heteroaryl;

R^(2a) and R^(2b) are each independently amino, halo, hydroxyl, cyano,C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₃-C₈ cycloalkyl, heterocycyclylalkyl, heteroaryl or aryl;

R^(2c) is H, amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈cycloalkyl, heterocycyclylalkyl, heteroaryl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(3b) joins with R^(4b) to form a carbocyclic orheterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to formoxo, a carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(4b) joins with R^(3b) to form a carbocyclic orheterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl or heterocyclylalkyl;

x and y are independently integers ranging from 0 to 2; and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein each occurrence of alkylene, aryl, heteroaryl, cycloalkyl,heterocyclyl, alkylaminyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy,cycloalkyl, hereocyclylalkyl, aminylalkyl, carboxyalkyl,aminylcarbonylalkyl, and carbocyclic and heterocyclic rings isoptionally substituted with one or more substituents unless otherwisespecified; and

provided that at least one occurrence of R^(3a), R^(3b), R^(4a) orR^(4b) is not H, and provided that when R¹ is indazolyl or naphthyl andone of R^(3a) or R^(3b) is methyl or hydroxyl methyl, then at least oneadditional occurrence of R^(3a) or R^(3b) or at least one occurrence ofR^(4a) or R^(4b) is not H.

In some other embodiments, the compound has the following structure(IIIa):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—; R⁸ isH, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C₃—Ccycloalkyl or heterocycloalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆ alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;and

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆ alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In some different embodiments, B is N. In other embodiments, B is C—CN.In other embodiments, B is CH.

In still different embodiments, A is N. In more embodiments, A is CH.

The structure of E in the compounds of structure (III) is notparticularly limited provided it is capable of forming a covalent bondwith a nucleophile, such as the cysteine residue at position 12 of aKRAS, HRAS or NRAS G12C mutant protein. Accordingly, moieties which arecapable of reaction with (e.g., by covalent bond formation) anucleophile are preferred. In certain embodiments, E is capable ofreacting in a conjugate addition manner (e.g., 1.4-conjugate addition)with an appropriately reactive nucleophile. In some embodiments, Ecomprises conjugated pi bonds such that delocalization of electronsresults in at least one atom (e.g., a carbon atom) having a positivecharge, partial positive charge or a polarized bond. In otherembodiments, E comprises one or more bonds wherein the electronegativityof the two atoms forming the bonds is sufficiently different such that apartial positive charge (e.g., by polarization of the bond) resides onone of the atoms, for example on a carbon atom. E moieties comprisingcarbon-halogen bonds, carbon-oxygen bonds or carbon bonds to variousleaving groups known in the art are examples of such E moieties.

In certain embodiments of the foregoing, E has the following structure:

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR S(═O)₂—;

R⁸ is H, C₁-C₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R⁸ is H, —OH, —CN or C₁-C₆ alkyl; and

when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;

when

is a triple bond; then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In certain embodiments when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R⁹ andR¹⁰ join to form a carbocyclic or heterocyclic ring.

In some of the foregoing embodiments, Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂—or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR⁸ is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodiments R^(8′)is H. In other embodiments, R^(8′) is —CN. In other embodiments, R^(8′)is —OH.

Accordingly, in some embodiments, the compound has one of the followingstructures (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg):

In some embodiments, the compound has one of structures (IIIa), (IIIb),(IIIc), (IIId), (IIIe), (IIIf) or (IIIg).

In any of the foregoing embodiments of the compounds of structure (III),(IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg) B is N. In someother of the foregoing embodiments of the compounds of structure (III),(IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg), B is C—CN. Inany of the foregoing embodiments of the compounds of structure (III),(IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg) B is CH. In anyof the foregoing embodiments of the compounds of structure (III),(IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg) A is N. In anyof the foregoing embodiments of the compounds of structure (III),(IIIa), (IIIb), (IIIc), (IIId), (IlIe), (IIIf) or (IIIg) A is CH.

Without wishing to be bound by theory, Applicants believe correctselection of the R¹ substituent may play a part in the compounds'inhibitory activity (e.g., against KRAS, HRAS or NRAS G12C). In someembodiments, R¹ is aryl or heterocyclyl (e.g., heteroaryl or aliphaticheterocyclyl), each of which is optionally substituted with one or moresubstituents. In some embodiments, R¹ is capable of reversibleinteraction with KRAS, HRAS or NRAS G12C mutant protein. In someembodiments R¹ has high affinity towards KRAS, HRAS or NRAS and ishighly specific towards G12C KRAS, HRAS or NRAS. In some embodiments R¹is capable of hydrophobic interaction with KRAS, HRAS or NRAS G12C. Insome embodiments R¹ is able to form hydrogen bonds with various residuesof G12C KRAS, HRAS or NRAS protein.

In any of the foregoing embodiments, R¹ is aryl. For example in someembodiments at least one occurrence of R^(3a), R^(3b), R^(4a) or R^(4b)is not H, and R¹ is phenyl. In other embodiments R¹ is naphthyl. R¹ issubstituted or unsubstituted. In some specific embodiments, R¹ issubstituted with one or more substituents. For example, in someembodiments R¹ is substituted with halo, cyano, amino, hydroxyl, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, heteroarylalkyloxy or C₁-C₆alkylcarbonyloxy, or combinations thereof. In some other embodiments R¹is substituted with halo, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy or C₁-C₆ alkylcarbonyloxy, or combinations thereof. In some evenmore embodiments, R¹ is substituted with fluoro or hydroxyl, orcombinations thereof.

In some more specific embodiments, R¹ has one of the followingstructures:

In some more specific embodiments, R¹ has one of the followingstructures:

In some more specific embodiments, R¹ has one of the followingstructures:

In some other embodiments, R¹ has one of the following structures:

In some different embodiments of the foregoing compounds, R¹ isheteroaryl, for example a heteroaryl comprising nitrogen. In otherembodiments, R¹ is indazolyl or quinolinyl. In more embodiments, R¹ isheteroaryl which is substituted with one or more substituents. Forexample, in certain embodiments, R¹ is substituted with hydroxyl, haloor C₁-C₆ alkyl, or both, for example hydroxyl or C₁-C₆ alkyl, or both.

In some other embodiments of structure (III), R^(2a) and R^(2b) are eachindependently amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈cycloalkyl, heterocycyclylalkyl, heteroaryl or aryl; and R^(2c) is H,amino, halo, hydroxyl, cyano, C₁-C₆ alkyl, C₁-C₆ alkyl amino, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₈ cycloalkyl,heterocycyclylalkyl, heteroaryl or aryl. In some embodiments, R^(2a),R^(2b) and/or R^(2c) are CF₃. In some of the foregoing embodimentsR^(2c) is H. In other of any of the foregoing embodiments, R^(2a) andR^(2b) are each halo. For example, in some embodiments R^(2a) is fluoro,and in other embodiments, R^(2b) is chloro. In different embodimentsR^(2a) is fluoro, and R^(2b) is chloro.

In some more specific embodiments, the compounds have the followingstructure (IIIh):

For example, in even further different embodiments, the compounds haveone of the following structures (III) or (IIIj):

In other embodiments, the compound has one of the following structures:

wherein R^(3a), R^(3b), R^(4a) and R^(4b) are independently —OH, —NH₂,—CO₂H, halo, cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or wherein R^(3a),R^(3b), R^(4a) and R^(4b) are independently —OH, —NH₂, —CO₂H, halo,cyano, unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl. For example, in some of theforegoing embodiments R^(3a), R^(3b), R^(4a) and R^(4b) areindependently unsubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl orhydroxylalkly. In some of these embodiments, C₁-C₆ alkyl is methyl,ethyl or isopropyl.

In other embodiments, R^(3a) and R^(3b) join to form oxo or acarbocyclic ring; or wherein R^(4a) and R^(4b) join to form oxo, or acarbocyclic ring, for example cyclopropyl.

In yet more of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl; and

R⁹ and R¹⁰ are each independently H, halo, cyano, carboxyl, C₁-C₆ alkyl,alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl,heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R⁹ and R¹⁰ join toform a carbocyclic, heterocyclic or heteroaryl ring.

In still other of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl; and

R¹⁰ is H, C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

The Q moiety is typically selected to optimize the reactivity (i.e.,electrophilicity) of E. In some of the foregoing embodiments Q is—C(═O)—, NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—. In certain of the foregoingembodiments, Q is —C(═O)—. In other embodiments, Q is —S(═O)₂—. In stillmore embodiments, Q is —NR⁸C(═O)—. In still more different embodiments,Q is —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodimentsR^(8′) is H. In other embodiments, R^(8′) is —CN. In other embodiments,R^(8′) is —OH.

In some of the foregoing embodiments, R⁸ is H. In other of theseembodiments, R⁸ is hydroxylalkyl, for example in some embodiments thehydroxylalkyl is 2-hydroxylalkyl.

In some of any one of the foregoing embodiments, at least one of R⁹ orR¹⁰ is H. For example, in some embodiments each of R⁹ and R¹⁰ are H.

In other of the foregoing embodiments, R¹⁰ is alkylaminylalkyl. In someof these embodiments, R¹⁰ has the following structure:

In other embodiments, R¹⁰ is hydroxylalkyl, such as 2-hydroxylalkyl.

In some other different embodiments of the foregoing embodiments, R⁹ andR¹⁰ join to form a carbocyclic ring. For example, in some of theseembodiments the carbocyclic ring is a cyclopentene, cyclohexene orphenyl ring. In other embodiments, the carbocyclic ring is acyclopentene or cyclohexene ring. In other embodiments, the carbocyclicring is a phenyl ring, for example a phenyl ring having the followingstructure:

In some of any of the foregoing embodiments E is an electrophile capableof bonding with a KRAS, HRAS or NRAS protein comprising G12C mutation.In some embodiments, the electrophile E is capable of forming anirreversible covalent bond with a G12C mutant KRAS, HRAS or NRASprotein. In some cases, the electrophile E may bind with the cysteineresidue at the position 12 of a G12C mutant KRAS, HRAS or NRAS protein.In various embodiments of any of the foregoing, E has one of thefollowing structures:

In some embodiments, E has one of the following structures:

In other embodiments of any of the foregoing, E has one of the followingstructures:

In different embodiments, E has one of the following structures:

In some embodiments, E has the following structure:

In other embodiments, E has the following structure:

In some cases E has one of the following structures:

wherein:

R⁸ is H or C₁-C₆alkyl;

R⁹ is H, cyano or C₁-C₆alkyl, or R⁹ joins with R¹⁰ to form a carbocycle;

R¹⁰ is H or C₁-C₆alkyl or R¹⁰ joins with R⁹ to form a carbocycle and

R^(10a) is H or C₁-C₆alkyl.

In some embodiments E is

In some embodiments E is

In some embodiments E is H

In some of any of the foregoing embodiments, L¹ is a bond. In otherembodiments, L¹ is NR⁵. For example, in some of these embodiments, R⁵ isC₁-C₆alkyl. In other embodiments, L¹ is NH.

L² can be selected to provide proper spacing and/or orientation for theE group to form a bond with the KRAS, HRAS or NRAS protein. In some ofthe foregoing embodiments, L² is a bond. In other of the foregoingembodiments, L² is alkylene. In some embodiments, the alkylene issubstituted. In other embodiments the alkylene is unsubstituted. Forexample, in some embodiments L² is CH₂ or CH₂CH₂.

In certain embodiments, R^(3a) and R^(3b) are, at each occurrence,independently H, —OH, —NH₂, —CO₂H, halo, cyano, hydroxylalkly,aminylalkyl, carboxyalkyl or aminylcarbonyl, and R^(4a) and R^(4b) are,at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,provided at least one of R^(3a), R^(3b), R^(4a) or R^(4b) is not H.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H, —OH, hydroxylalkly, cyano, oraminylcarbonyl and R^(3b) and R^(4b) are H, provided at least one ofR^(3a) or R^(4a) is not H.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H or C₁-C₆ alkyl, provided at least one ofR^(3a), R^(3b), R^(4a) or R^(4b) is H. In some embodiments, at least oneof R^(3a), R^(4a), R^(3b) and R^(4b) is independently C₁-C₆ alkyl, suchas methyl. In some embodiments, one occurrence of R^(3a) is C₁-C₆ alkyl,such as methyl, and the remaining R^(3a) and each R^(4a) is H. In someother embodiments, two occurrences of R^(3a) are C₁-C₆ alkyl, such asmethyl, and the remaining R^(3a) and each R^(4a) is H. In some otherembodiments, one occurrence of R^(3a) and one occurrence of R^(4a) isindependently C₁-C₆ alkyl, such as methyl, and the remaining R^(3a) andR^(4a) are each H.

In certain other embodiments, R^(3a) and R^(4a) are H and R^(3b) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, carboxyalkyl or aminylcarbonyl,provided at least one of R^(3a), R^(3b), R^(4a) or R^(4b) is not H.

In any of the foregoing embodiments, at least one of R^(3a), R^(3b),R^(4a) or R^(4b) is H, provided at least one of R^(3a), R^(3b), R^(4a)or R^(4b) is not H.

In some embodiments, R^(3a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, carboxyalkyl or aminylcarbonyl, and R^(3b),R^(4a) and R^(4b) are H.

In other embodiments, R^(4a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, carboxyalkyl or aminylcarbonyl, and R^(3a),R^(3b) and R^(4b) are H.

In other embodiments, R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, carboxyalkyl or aminylcarbonyl, and R^(3b)joins with R^(4b) to form a carbocyclic or heterocyclic ring;

In still more embodiments, R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, carboxyalkyl or aminylcarbonyl, and R^(4b)joins with R^(3b) to form a carbocyclic or heterocyclic ring.

In other embodiments, R^(3a) and R^(3b) join to form a carbocyclic orheterocyclic ring. In other embodiments, R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring.

In still other embodiments, R^(3a) or R^(4a) is aminylcarbonyl. Forexample, in certain embodiments, the aminylcarbonyl is

In other embodiments, R^(3a) or R^(4a) is cyano. In other embodiments,R^(3a) or R^(4a) is —OH. In other embodiments, R^(3a) or R^(4a) ishydroxylalkyl, for example hydroxylmethyl.

In some embodiments of any of the foregoing compounds (e.g., thecompounds of structures (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe),(IIIf), (IIIg), (IIIh), (III) or (IIIj)), R¹ is aryl or heteroaryl andR^(2a), R^(2b) and R^(2c) are independently selected from H and halo,for example in some further embodiments R¹ is aryl or heteroaryl andR^(2a) and R^(2b) are independently selected from halo, such as chloroand fluoro, and R^(2c) is H. In some embodiments, R¹ is aryl orheteroaryl, R^(2a) is chloro, R^(2b) is fluoro and R^(2c) is H. In otherembodiments R¹ is aryl or heteroaryl, one of R^(2a) or R^(2b) is halo,such as chloro or fluoro, and the other one of R^(2a) or R^(2b) is H.

In some embodiments of any of the compounds described herein, C₁-C₆haloalkyl is CF₃ (e.g., when one or more of R^(2a), R^(2b) or R^(2c) isC₁-C₆ haloalkyl).

In some embodiments x is 0. In other embodiments x is 1. In still moreembodiments, x is 2. In different embodiments, y is 0. In some otherembodiments, y is 1. In yet still more embodiments, y is 2.

In some other particular embodiments of any of the foregoing compounds,x is 1, and y is 1. In other embodiments, x is 1 and, y is 2. In stillother embodiments x is 0, and y is 2. In more embodiments, x is 0, and yis 2.

In any of the foregoing embodiments, G¹ and G² are each independentlyselected from N and CH. In some embodiments, at least one of G¹ or G² isN. In some embodiments, each of G¹ and G² are N. In some embodiments,each of G¹ and G² are N and m¹ and m² are each 2. In some otherembodiments, at least one of G¹ or G² is CH. In other embodiments, eachof G¹ and G² are CH.

In any of the foregoing embodiments, B is N. In other of the foregoingembodiments, B is C—CN. In other of the foregoing embodiments, B is CH.

In other of the foregoing embodiments, A is N. In other of the foregoingembodiments, A is CH.

Some embodiments of the compounds include more than one stereoisomer.Other embodiments are directed to a single stereoisomer. In someembodiments the compounds are racemic (e.g., mixture of atropisomers),while in other embodiments the compounds are substantially a singleisomer, for example a substantially purified atropisomer.

In various different embodiments, the compound of structure (III) hasone of the structures set forth in Table 5 below. The compounds in Table5 were each prepared and analyzed by mass spectrometry and/or ¹H NMR.Experimental mass spectrometry data is included in Table 5. Exemplarysynthetic procedures are described in more detail below and in theExamples. General methods by which the compounds may be prepared areprovided below and indicated in Table 5.

TABLE 5 Representative Compounds of Structure (III) No. Structure NameMethod [M + H]⁺ III-1

1-((2R,5S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.10 III-2

1-((2R,5S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- methoxy- phenyl)quinazolin- 4-yl)-2,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U473.20 III-3

1-((3S)-4- (6-chloro-8- fluoro-7-(6- methyl-1H- indazol-7-yl)quinazolin-4- yl)-3-methyl- piperazin-1- yl)prop-2- en-1-one R 465.35III-4

1-((3S,5R)-4- ((R)-6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3,5- dimethyl- piperazin-1- yl)prop-2- en-1-one U459.25 III-5

1-(4-(6- chloro- 8-fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2- methyl- piperazin-1- yl)prop-2- en-1-one U 445.20 III-6

1-((2S,6R)-4- ((S)-(6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.25 III-7

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2,2- dimethyl- piperazin-1- yl)prop-2- en-1-one U 459.60 III-8

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2- (hydroxy- methyl) piperazin-1- yl)prop-2- en-1-one R 461.15III-9

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2,6- dimethyl- piperazin-1- yl)prop-2- en-1-one U 459.55 III-10

1-(7-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-4,7- diazaspiro [2.5]octan-4- yl)prop-2- en-1-one U 457.45 III-11

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2- (trifluoro- methyl) piperazin-1- yl)prop-2- en-1-one U 499.55III-12

1-((3R)-4- (6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- methyl- piperazin-1- yl)prop-2- en-1-one V 445.10III-13

1-((3R)-4- (6-chloro- 8-fluoro-7-(2- fluoro-6- methoxy- phenyl)quinazolin- 4-yl)-3- methyl- piperazin-1- yl)prop-2- en-1-one V 459.1III-14

1-((3S)-4- (6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- methyl- piperazin-1- yl)prop-2- en-1-one V 445.10III-15

1-((2S,6R)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.15 III-16

1-(5-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2,5- diazabicyclo [4.1.0.]heptan- 2-yl)prop-2- en-1-one U 443.05III-17

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-3,3- dimethyl- piperazin-1- yl)prop-2- en-1-one V 459.15 III-18

1-((2S,6S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.15 III-19

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-2- (difluoro- methyl) piperazin-1- yl)prop-2- en-1-one U 481.15III-20

1-((2S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2- methyl- piperazin- 1-yl)prop-2- en-1-one U 445.15III-21

1-((2R)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2- methyl- piperazin- 1-yl)prop-2- en-1-one U 445.05III-22

1-((2R,6R)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.20 III-23

1-((S)-4-((R)- 6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- methyl- piperazin- 1-yl)prop-2- en-1-one U 445.15III-24

1-((S)-4-((S)- 6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- methyl- piperazin- 1-yl)prop-2- en-1-one U 445.15III-25

1-((3S)- 4-(6-chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)quinazolin- 4-yl)-3- methyl- piperazin- 1-yl)prop-2- en-1-one R 465.25III-26

1-((2S,6R)- 4-(6-chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one R479.20 III-27

1-((2S,6R)- 4-(6-chloro-8- fluoro-7-(3- hydroxy- naphthalen-1-yl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one R491.20 III-28

1-((3R,5S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.1 III-29

1-((2S,6R)-4- ((R)-6-chloro- 8-fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.25 III-30

1-((3S)-4- (6-chloro-8- fluoro-7-(3- hydroxy- naphthalen-1-yl)quinazolin- 4-yl)-3- methyl- piperazin- 1-yl)prop-2- en-1-one R477.30 III-31

1-(4-(6- chloro-8- fluoro-7- (2-fluoro-6- hydroxy- phenyl) quinazolin-4-yl)-4,7- diazaspiro [2.5]octan-7- yl)prop-2- en-1-one U 457.1 III-32

1-((3S)-4- (6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- ethyl- piperazin- 1-yl)prop-2- en-1-one U 459.30III-33

1-((3R,5R)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.25 III-34

1-((3S)-4- (6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- isopropyl- piperazin- 1-yl)prop-2- en-1-one U473.30 III-35

1-((2S,6R)- 4-(6-chloro-8- fluoro-7-(6- methyl-1H- indazol-7-yl)quinazolin- 4-yl)-2,6- dimethyl- piperazin- 1-yl)prop-2- en-1-one R479.30 III-36

1-((3S,5R)-4- ((S)-(6- chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.25 III-37

1-((3S,5S)- 4-(6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one U459.30 III-38

4-acryloyl-1- (6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl) piperazin-2- one U 445.10 III-39

1-((3R)-4- (6-chloro-8- fluoro-7-(2- fluoro-6- hydroxy- phenyl)quinazolin- 4-yl)-3- (hydroxy- methyl) piperazin- 1-yl)prop-2- en-1-oneU 461.15 III-40

1-((3S,5R)- 4-(6-chloro-8- fluoro-7-(5- methyl-1H- indazol-4-yl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one R479.30 III-41

1-((3S,5R)-4- (6-chloro-8- fluoro-7-(3- hydroxy- naphthalen-1-yl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one R491.3 III-42

1-((3S,5R)-4- (6-chloro-8- fluoro-7-(6- methyl-1H- indazol-7-yl)quinazolin- 4-yl)-3,5- dimethyl- piperazin- 1-yl)prop-2- en-1-one R479.30 III-43

4-((3R,5S)-4- acryloyl-3,5- dimethyl- piperazin-1- yl)(6-chloro-8-fluoro-7-(2- fluoro-6- hydroxy- phenyl) quinoline-3- carbonitrile W483.15

It is understood that in the present description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

Furthermore, all compounds of the invention which exist in free base oracid form can be converted to their pharmaceutically acceptable salts bytreatment with the appropriate inorganic or organic base or acid bymethods known to one skilled in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques.

The following General Reaction Schemes illustrate exemplary methods ofmaking compounds of compounds of structure (III):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein x, y, R¹, R^(2a), R^(2b), R^(2c), R^(3a), R^(3b), R^(4a),R^(4b), G¹, G², L¹, L², A, B and E are as defined herein. It isunderstood that one skilled in the art may be able to make thesecompounds by similar methods or by combining other methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make, in a similar manner as described below, othercompounds of structure (I) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention.

Certain embodiments of the compounds of structure (III) are preparedaccording to General reaction Scheme 11 above. Other general methods forpreparation of compounds of structure (III) are provided below.

Embodiments of the compound of structure (III) (e.g., compound U-8) canbe prepared according to General Reaction Scheme 21 (“Method U”),wherein R¹, R⁹ and R¹⁰ are as defined herein above. Referring to GeneralReaction Scheme 21, compounds of structure U-1 are purchased fromcommercial sources and treated under Suzuki conditions to yield U-2.Chlorination of U-2 with N-chlorosuccinimide yields U-3, which iscyclized to quinazolinol U-4. Chlorination of U-4 and reaction with anappropriate heterocycle (e.g., U-6) yields U-7. Treatment of U-7according to the general procedures described above yields U-8.

Embodiments of the compound of structure (I) (e.g., compound V-4) can beprepared according to General Reaction Scheme 22 (“Method V”), whereinx, y R¹, R^(3a), R^(3b), R^(4a), R^(4b), R⁹ and R¹⁰ are as definedherein above. Referring to General Reaction Scheme 22, compounds ofstructure V-1 are purchased from commercial sources or preparedaccording to methods. Reaction of V-1 with an appropriate heterocycle(U-6) yields V-2. Alternatively, V-2 can be prepared from V-1 via atwo-step procedure through V-5 intermediate. The desired R¹ moiety isthen installed using mixed metal catalyzed chemistry and an appropriatearyl or heteroaryl bromide (R¹—Br) to yield V-3. Treatment of V-3according to the general procedures described above yields V-4.

Embodiments of the compound of structure (I) (e.g., compound W-10) canbe prepared according to General Reaction Scheme 23 (“Method W”),wherein x, y R¹, R^(3a), R^(3b), R^(4a), R^(4b), R⁹ and R¹⁰ are asdefined herein above. Referring to General Reaction Scheme 23, compoundsof structure A-2 are prepared as described above. Chlorination of A-2with N-chlorosuccinimide yields W-1, which is cyclized to N-3 via atwo-step procedure. Chlorination of W-3 and reaction with an appropriateheterocycle (e.g., U-6) yields W-5. Treatment of W-5 under Suzukiconditions yields W-6. Saponification followed by amination then yieldsamide W-8. Treatment of W-8 according to the general proceduresdescribed above yields W-9. Finally, W-10 can be obtained by treatmentof W-9 with an appropriate dehydrating reagent, such as trifluoroaceticanhydride.

Additional general synthetic methods are provided in the Examples. Itwill be apparent to one of ordinary skill in the art that all compoundsof structure (I), (II) and (III) can be prepared according to one ormore of the methods described herein or otherwise known in the art. Itwill also be apparent that in some instances it will be necessary to usea differently substituted starting material and/or protecting groups toarrive at the desired compound when following the general proceduresdescribed herein. Various substituents may also be added at variouspoints in the synthetic scheme to prepare the desired compound.

Further, one skilled in the art will recognize that certainmodifications to the above schemes and those provided in the examplesare possible to prepare different embodiments of compounds of structure(I), (II) and (III). For example, for ease of illustration the GeneralReaction Schemes above depict preparation of compounds of structure (I),(II) and (III) wherein R^(2a), R^(2b) and R^(2c) are fluoro, chloro andH, respectively. However, it will be apparent to one of ordinary skillin the art that differently substituted compounds of structure (I), (II)and (III) can be prepared according the general methods provided hereinby using differently substituted starting materials and/or adding thedesired substituent using methods known in the art.

Further, the General Reaction Schemes depict compounds comprising apiperazine ring, but other compounds can be prepared according to theprovided methods by using alternative reagents, for example a reagenthaving the following structure:

can be used in place of the piperazine illustrated in the above schemes.One of ordinary skill in the art will also readily recognize thatcompounds wherein L¹ is NR⁵ can be prepared by substituting thepiperazine illustrated in the above schemes with a heterocycle havingthe following structure:

where R is H, a protecting group or C₁-C₆alkyl.

It will also be appreciated by those skilled in the art that in theprocesses for preparing the compounds described herein the functionalgroups of intermediate compounds may need to be protected by suitableprotecting groups. Such functional groups include, but are not limitedto, hydroxy, amino, mercapto and carboxylic acid. Suitable protectinggroups for hydroxy include trialkylsilyl or diarylalkylsilyl (forexample, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters. Protectinggroups are optionally added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Green, T.W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protectinggroup may also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

Pharmaceutical Compositions

Other embodiments are directed to pharmaceutical compositions. Thepharmaceutical composition comprises any one (or more) of the foregoingcompounds and a pharmaceutically acceptable carrier. In someembodiments, the pharmaceutical composition is formulated for oraladministration. In other embodiments, the pharmaceutical composition isformulated for injection. In still more embodiments, the pharmaceuticalcompositions comprise a compound as disclosed herein and an additionaltherapeutic agent (e.g., anticancer agent). Non-limiting examples ofsuch therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that are used in someembodiments. An exemplary dosage is 10 to 30 mg per day. The exactdosage will depend upon the route of administration, the form in whichthe compound is administered, the subject to be treated, the body weightof the subject to be treated, and the preference and experience of theattending physician.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes are used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. In some embodiments, dosing is about once, twice, threetimes, four times, five times, six times, or more than six times perday. In other embodiments, dosing is about once a month, once every twoweeks, once a week, or once every other day. In another embodiment acompound of the invention and another agent are administered togetherabout once per day to about 6 times per day. In another embodiment theadministration of a compound of the invention and an agent continues forless than about 7 days. In yet another embodiment the administrationcontinues for more than about 6, 10, 14, 28 days, two months, sixmonths, or one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

In some embodiments, the compounds of the invention are administered indosages. It is known in the art that due to intersubject variability incompound pharmacokinetics, individualization of dosing regimen isnecessary for optimal therapy. Dosing for a compound of the inventionmay be found by routine experimentation in light of the instantdisclosure.

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofstructure (I), (II) or (III) and a pharmaceutically acceptablediluent(s), excipient(s), or carrier(s). In certain embodiments, thecompounds described are administered as pharmaceutical compositions inwhich compounds of structure (I), (II) or (III) are mixed with otheractive ingredients, as in combination therapy. Encompassed herein areall combinations of actives set forth in the combination therapiessection below and throughout this disclosure. In specific embodiments,the pharmaceutical compositions include one or more compounds ofstructure (I), (II) or (III).

A pharmaceutical composition, as used herein, refers to a mixture of acompound of structure (I), (II) or (III) with other chemical components,such as carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients. In certain embodiments,the pharmaceutical composition facilitates administration of thecompound to an organism. In some embodiments, practicing the methods oftreatment or use provided herein, therapeutically effective amounts ofcompounds of structure (I), (II) or (III) provided herein areadministered in a pharmaceutical composition to a mammal having adisease, disorder or medical condition to be treated. In specificembodiments, the mammal is a human. In certain embodiments,therapeutically effective amounts vary depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds described herein are usedsingly or in combination with one or more therapeutic agents ascomponents of mixtures.

In one embodiment, one or more compounds of structure (I), (II) or (III)is formulated in an aqueous solutions. In specific embodiments, theaqueous solution is selected from, by way of example only, aphysiologically compatible buffer, such as Hank's solution, Ringer'ssolution, or physiological saline buffer. In other embodiments, one ormore compound of structure (I), (II) or (III) is/are formulated fortransmucosal administration. In specific embodiments, transmucosalformulations include penetrants that are appropriate to the barrier tobe permeated. In still other embodiments wherein the compounds describedherein are formulated for other parenteral injections, appropriateformulations include aqueous or nonaqueous solutions. In specificembodiments, such solutions include physiologically compatible buffersand/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein are formulated bycombining the active compounds with, e.g., pharmaceutically acceptablecarriers or excipients. In various embodiments, the compounds describedherein are formulated in oral dosage forms that include, by way ofexample only, tablets, powders, pills, dragees, capsules, liquids, gels,syrups, elixirs, slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical compositions are formulated in a formsuitable for parenteral injection as sterile suspensions, solutions oremulsions in oily or aqueous vehicles. Parenteral injection formulationsoptionally contain formulatory agents such as suspending, stabilizingand/or dispersing agents. In specific embodiments, pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. In additional embodiments,suspensions of the active compounds (e.g., compounds of structure (I),(II) or (III)) are prepared as appropriate oily injection suspensions.Suitable lipophilic solvents or vehicles for use in the pharmaceuticalcompositions described herein include, by way of example only, fattyoils such as sesame oil, or synthetic fatty acid esters, such as ethyloleate or triglycerides, or liposomes. In certain specific embodiments,aqueous injection suspensions contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension contains suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, in other embodiments, the active ingredient is in powderform for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In still other embodiments, the compounds of structure (I), (II) or(III) are administered topically. The compounds described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compositions optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

In yet other embodiments, the compounds of structure (I), (II) or (III)are formulated for transdermal administration. In specific embodiments,transdermal formulations employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In various embodiments, such patches are constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.In additional embodiments, the transdermal delivery of the compounds ofstructure (I), (II) or (III) is accomplished by means of iontophoreticpatches and the like. In certain embodiments, transdermal patchesprovide controlled delivery of the compounds of structure (I), (II) or(III). In specific embodiments, the rate of absorption is slowed byusing rate-controlling membranes or by trapping the compound within apolymer matrix or gel. In alternative embodiments, absorption enhancersare used to increase absorption. Absorption enhancers or carriersinclude absorbable pharmaceutically acceptable solvents that assistpassage through the skin. For example, in one embodiment, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

In other embodiments, the compounds of structure (I), (II) or (III) areformulated for administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of any of compound ofstructure (I), (II) or (III) are conveniently delivered in the form ofan aerosol spray presentation from pressurized packs or a nebuliser,with the use of a suitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In specific embodiments, the dosage unit of apressurized aerosol is determined by providing a valve to deliver ametered amount. In certain embodiments, capsules and cartridges of, suchas, by way of example only, gelatin for use in an inhaler or insufflatorare formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

In still other embodiments, the compounds of structure (I), (II) or(III) are formulated in rectal compositions such as enemas, rectal gels,rectal foams, rectal aerosols, suppositories, jelly suppositories, orretention enemas, containing conventional suppository bases such ascocoa butter or other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are optionally used as suitable. Pharmaceuticalcompositions comprising a compound of structure (I), (II) or (III) aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofstructure (I), (II) or (III), described herein as an active ingredient.The active ingredient is in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.All tautomers of the compounds described herein are included within thescope of the compounds presented herein. Additionally, the compoundsdescribed herein encompass unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein. In addition, the pharmaceuticalcompositions optionally include other medicinal or pharmaceuticalagents, carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of structure (I), (II) or (III) illustratively takes the formof a liquid where the agents are present in solution, in suspension orboth. Typically when the composition is administered as a solution orsuspension a first portion of the agent is present in solution and asecond portion of the agent is present in particulate form, insuspension in a liquid matrix. In some embodiments, a liquid compositionincludes a gel formulation. In other embodiments, the liquid compositionis aqueous.

In certain embodiments, useful aqueous suspensions contain one or morepolymers as suspending agents. Useful polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein comprise a mucoadhesive polymer, selected for examplefrom carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of structure(I), (II) or (III). The term “solubilizing agent” generally includesagents that result in formation of a micellar solution or a truesolution of the agent. Certain acceptable nonionic surfactants, forexample polysorbate 80, are useful as solubilizing agents, as canophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. The container(s) optionally have a sterile accessport (for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical compositions is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack for example contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods

Embodiments of the present invention provide a method of inhibitingRAS-mediated cell signaling comprising contacting a cell with aneffective amount of one or more compounds disclosed herein. Inhibitionof RAS-mediated signal transduction can be assessed and demonstrated bya wide variety of ways known in the art. Non-limiting examples include ashowing of (a) a decrease in GTPase activity of RAS; (b) a decrease inGTP binding affinity or an increase in GDP binding affinity; (c) anincrease in K off of GTP or a decrease in K off of GDP; (d) a decreasein the levels of signaling transduction molecules downstream in the RASpathway, such as a decrease in pMEK level; and/or (e) a decrease inbinding of RAS complex to downstream signaling molecules including butnot limited to Raf. Kits and commercially available assays can beutilized for determining one or more of the above.

Embodiments also provide methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to conditions implicated by G12CKRAS, HRAS or NRAS mutation, G12C HRAS mutation and/or G12C NRASmutation (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound of structure(I), (II) or (III) to a subject in need thereof. In some embodiments,the pharmaceutical composition comprises a compound of structure (I). Insome embodiments, the pharmaceutical composition comprises a compound ofstructure (II). In some embodiments, the pharmaceutical compositioncomprises a compound of structure (III). In some embodiments, the canceris mediated by a KRAS, HRAS or NRAS G12C mutation. In other embodiments,the cancer is pancreatic cancer, colon cancer, MYH associated polyposis,colorectal cancer or lung cancer.

In some embodiments the invention provides method of treating a disorderin a subject in need thereof, wherein the said method comprisesdetermining if the subject has a KRAS, HRAS or NRAS G12C mutation and ifthe subject is determined to have the KRAS, HRAS or NRAS G12C mutation,then administering to the subject a therapeutically effective dose of atleast one compound of structure (I), (II) or (III) or a pharmaceuticallyacceptable salt, ester, prodrug, tautomer, solvate, hydrate orderivative thereof.

The disclosed compounds strongly inhibit anchorage-independent cellgrowth and therefore have the potential to inhibit tumor metastasis.Accordingly, in another embodiment the disclosure provides a method forinhibiting tumor metastasis, the method comprising administering aneffective amount a pharmaceutical composition of comprising any of thecompounds disclosed herein and a pharmaceutically acceptable carrier toa subject in need thereof.

KRAS, HRAS or NRAS G12C mutations have also been identified inhematological malignancies (e.g., cancers that affect blood, bone marrowand/or lymph nodes). Accordingly, certain embodiments are directed toadministration of a disclosed compounds (e.g., in the form of apharmaceutical composition) to a patient in need of treatment of ahematological malignancy. Such malignancies include, but are not limitedto leukemias and lymphomas. For example, the presently disclosedcompounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/or otherleukemias. In other embodiments, the compounds are useful for treatmentof lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin'slymphoma.

Determining whether a tumor or cancer comprises a G12C KRAS, HRAS orNRAS mutation can be undertaken by assessing the nucleotide sequenceencoding the KRAS, HRAS or NRAS protein, by assessing the amino acidsequence of the KRAS, HRAS or NRAS protein, or by assessing thecharacteristics of a putative KRAS, HRAS or NRAS mutant protein. Thesequence of wild-type human KRAS, HRAS or NRAS is known in the art,(e.g. Accession No. NP203524).

Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotidesequence are known by those of skill in the art. These methods include,but are not limited to, polymeRASe chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) assays, polymeRASe chain reaction-singlestrand conformation polymorphism (PCR-SSCP) assays, real-time PCRassays, PCR sequencing, mutant allele-specific PCR amplification (MASA)assays, direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, samples are evaluated for G12C KRAS, HRASor NRAS mutations by real-time PCR. In real-time PCR, fluorescent probesspecific for the KRAS, HRAS or NRAS G12C mutation are used. When amutation is present, the probe binds and fluorescence is detected. Insome embodiments, the KRAS, HRAS or NRAS G12C mutation is identifiedusing a direct sequencing method of specific regions (e.g., exon 2and/or exon 3) in the KRAS, HRAS or NRAS gene. This technique willidentify all possible mutations in the region sequenced.

Methods for detecting a mutation in a KRAS, HRAS or NRAS protein areknown by those of skill in the art. These methods include, but are notlimited to, detection of a KRAS, HRAS or NRAS mutant using a bindingagent (e.g., an antibody) specific for the mutant protein, proteinelectrophoresis and Western blotting, and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a G12C KRAS,HRAS or NRAS mutation can use a variety of samples. In some embodiments,the sample is taken from a subject having a tumor or cancer. In someembodiments, the sample is taken from a subject having a cancer ortumor. In some embodiments, the sample is a fresh tumor/cancer sample.In some embodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

Embodiments also relate to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, cancer inadolescents, adrenocortical carcinoma childhood, AIDS-related cancers(e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer,bladder cancer, bone cancer, brain stem glioma, brain tumor, breastcancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypicalteratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervicalcancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer,Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, isletcell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer(NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer,ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pleuropulmonary blastoma, primary centralnervous system (CNS) lymphoma, prostate cancer, rectal cancer,transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivarygland cancer, skin cancer, stomach (gastric) cancer, small cell lungcancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, transitional cell cancer of the renal pelvis and ureter,trophoblastic tumor, unusual cancers of childhood, urethral cancer,uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer.In some embodiments, said method relates to the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e. g., psoriasis), restenosis, or prostate (e. g., benignprostatic hypertrophy (BPH)).

In certain particular embodiments, the invention relates to methods fortreatment of lung cancers, the methods comprise administering aneffective amount of any of the above described compound (or apharmaceutical composition comprising the same) to a subject in needthereof. In certain embodiments the lung cancer is a non-small cell lungcarcinoma (NSCLC), for example adenocarcinoma, squamous-cell lungcarcinoma or large-cell lung carcinoma. In other embodiments, the lungcancer is a small cell lung carcinoma. Other lung cancers treatable withthe disclosed compounds include, but are not limited to, glandulartumors, carcinoid tumors and undifferentiated carcinomas.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative of said compounds, according to the methods ofthis invention include, for example, subjects that have been diagnosedas having acute myeloid leukemia, acute myeloid leukemia, cancer inadolescents, adrenocortical carcinoma childhood, AIDS-related cancers(e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer,bladder cancer, bone cancer, brain stem glioma, brain tumor, breastcancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypicalteratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervicalcancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer,Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, isletcell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer(NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer,ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma,paranasal sinus and nasal cavity cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pleuropulmonary blastoma, primary centralnervous system (CNS) lymphoma, prostate cancer, rectal cancer,transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivarygland cancer, skin cancer, stomach (gastric) cancer, small cell lungcancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, transitional cell cancer of the renal pelvis and ureter,trophoblastic tumor, unusual cancers of childhood, urethral cancer,uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer.In some embodiments subjects that are treated with the compounds of theinvention include subjects that have been diagnosed as having anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e. g., psoriasis), restenosis, or prostate (e. g., benignprostatic hypertrophy (BPH)).

Embodiments further provide methods of modulating a G12C Mutant KRAS,HRAS or NRAS protein activity by contacting the protein with aneffective amount of a compound of the invention. Modulation can beinhibiting or activating protein activity. In some embodiments, theinvention provides methods of inhibiting protein activity by contactingthe G12C Mutant KRAS, HRAS or NRAS protein with an effective amount of acompound of the invention in solution. In some embodiments, theinvention provides methods of inhibiting the G12C Mutant KRAS, HRAS orNRAS protein activity by contacting a cell, tissue, organ that expressthe protein of interest. In some embodiments, the invention providesmethods of inhibiting protein activity in subject including but notlimited to rodents and mammal (e.g., human) by administering into thesubject an effective amount of a compound of the invention. In someembodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%,70%, 80%, or 90%. In some embodiments, the percentage of inhibitingexceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the invention provides methods of inhibiting KRAS,HRAS or NRAS G12C activity in a cell by contacting said cell with anamount of a compound of the invention sufficient to inhibit the activityof KRAS, HRAS or NRAS G12C in said cell. In some embodiments, theinvention provides methods of inhibiting KRAS, HRAS or NRAS G12Cactivity in a tissue by contacting said tissue with an amount of acompound of the invention sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said tissue. In some embodiments, the inventionprovides methods of inhibiting KRAS, HRAS or NRAS G12C activity in anorganism by contacting said organism with an amount of a compound of theinvention sufficient to inhibit the activity of KRAS, HRAS or NRAS G12Cin said organism. In some embodiments, the invention provides methods ofinhibiting KRAS, HRAS or NRAS G12C activity in an animal by contactingsaid animal with an amount of a compound of the invention sufficient toinhibit the activity of KRAS, HRAS or NRAS G12C in said animal. In someembodiments, the invention provides methods of inhibiting KRAS, HRAS orNRAS G12C activity in a mammal by contacting said mammal with an amountof a compound of the invention sufficient to inhibit the activity ofKRAS, HRAS or NRAS G12C in said mammal. In some embodiments, theinvention provides methods of inhibiting KRAS, HRAS or NRAS G12Cactivity in a human by contacting said human with an amount of acompound of the invention sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said human. In other embodiments, the presentinvention provides methods of treating a disease mediated by KRAS, HRASor NRAS G12C activity in a subject in need of such treatment.

Other embodiments provide methods for combination therapies in which anagent known to modulate other pathways, or other components of the samepathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative thereof. In one aspect, such therapy includes butis not limited to the combination of one or more compounds of theinvention with chemotherapeutic agents, therapeutic antibodies, andradiation treatment, to provide a synergistic or additive therapeuticeffect.

Many chemotherapeutics are presently known in the art and can be used incombination with the compounds of the invention. In some embodiments,the chemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomeRASe inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomeRASe inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

Embodiments further relate to a method for using the compounds orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or 1-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the invention can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i. e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, andMMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

Different embodiments also relate to a method of and to a pharmaceuticalcomposition for treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative thereof, or an isotopically-labeled derivativethereof, and an amount of one or more therapeutic agents use for thetreatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g. codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen ornedocromil; anti-infectives, e.g. cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g. methapyrilene; anti-inflammatories, e.g.beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators,e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol,reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine,tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments are used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimize the activity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesteRASe agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, ρ3-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the invention include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, tRAStuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentinvention with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present invention withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentinvention with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present invention with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present invention with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

In other embodiments, agents useful in methods for combination therapywith one or more compounds of structure (I), (II) or (III) include, butare not limited to: Erlotinib, Afatinib, Iressa, GDC0941, MLN1117,BYL719 (Alpelisib), BKM120 (Buparlisib), CYT387, GLPG0634, Baricitinib,Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib, TG101348,Crizotinib, tivantinib, AMG337, cabozantinib, foretinib, onartuzumab,NVP-AEW541, Dasatinib, Ponatinib, saracatinib, bosutinib, trametinib,selumetinib, cobimetinib, PD0325901, RO5126766, Axitinib, Bevacizumab,Bostutinib, Cetuximab, Crizotinib, Fostamatinib, Gefitinib, Imatinib,Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib,Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656,Trastuzumab, Tofacitinib, Vandetanib, Vemurafenib, Irinotecan, Taxol,Docetaxel, Rapamycin or MLN0128.

Further therapeutic agents that can be combined with a compound of theinvention are found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the invention will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of theinvention and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the invention and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples, andthroughout the specification and claims, molecules with a single chiralcenter, unless otherwise noted, exist as a racemic mixture. Thosemolecules with two or more chiral centers, unless otherwise noted, existas a racemic mixture of diastereomers. Single enantiomers/diastereomersmay be obtained by methods known to those skilled in the art.

EXAMPLES

The following examples are provided for exemplary purposes. Othercompounds of structure (I), (II) or (III) were prepared according to thefollowing general procedures as indicated in Tables 1, 3 and 5.

Example 11-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 1 provides an exemplary preparation according to GeneralSynthetic Method A.

3-Bromo-2-fluorobenzenamine

To a mixture of 1-bromo-2-fluoro-3-nitrobenzene (50 g, 228.4 mmol), HOAc(41.1 g, 685.2 mmol), EtOH (420 mL) and H₂O (140 mL) at roomtemperature, iron powder (38.4 g, 685.2 mmol) was added portion-wise.The resulting mixture was stirred at room temperature for 16 h and thenwas neutralized with NaOH (5 N) solution. The mixture was extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (petroleum ether) to affordthe crude product (48 g) as a brown oil.

N-(3-Bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide

A mixture of 2,2,2-Trichloroethane-1,1-diol (37.7 g, 228.6 mmol) andNa₂SO₄ (243.5 g, 1714.5 mmol) were dissolved in water (600 mL) at 60° C.(form a clear solution). 3-Bromo-2-fluorobenzenamine (36 g, 190.5 mmol)was added to the mixture. The mixture was stirred at 60° C. for 1 h, andthen 35% aqueous HCl (31.7 mL, 381 mmol) was added. The resultingmixture was stirred at 60° C. for 1 h. To this mixture, hydroxylaminehydrochloride (65.7 g, 952.5 mmol) was added. The resulting mixture wasstirred at 60° C. for 4 h and then stirred at 100° C. for 16 h. Theyellow precipitate was formed. The mixture was allowed to cool to roomtemperature. The solid was collected by filtration, rinsed with water,and dried to afford the desired product (38.9 g, 78% yield).

6-Bromo-7-fluoroindoline-2,3-dione

To the concentrated sulfuric acid (270 mL) at 60° C.,N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide (29.4 g, 113.1mmol) was added. The resulting mixture was stirred at 90° C. for 1 h.The TLC showed complete consumption of the starting material. Thereaction mixture was allowed to cool to room temperature and poured intoice to get yellow precipitate. The mixture was extracted with ethylacetate. The organic layer was washed with water, saturated NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (dichloromethane/ethylacetate=200:1 to 20:1) to afford the desired product as a yellow solid(18.9 g, 68% yield). ESI-MS m/z: 278.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6)δ: 11.75 (s, 1H), 7.39 (dd, J=5.7, 7.9 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H).

2-Amino-4-bromo-3-fluorobenzoic Acid

To a mixture of 6-bromo-7-fluoroindoline-2,3-dione (18.9 g, 77.5 mmol)in 2 N NaOH (350 mL) at 0° C., H₂O₂(30%, 40 mL) was added. The mixturewas stirred at room temperature for 16 h. The mixture was quenched withNa₂SO₃, and the mixture was acidified with conc. HCl to adjust pH to 2.The precipitate was collected by filtration and dried to afford thedesired product as a white solid (17 g, 94% yield).

2-Amino-4-bromo-5-chloro-3-fluorobenzoic Acid

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (17 g, 72.6 mmol)in DMF (200 mL) at room temperature, NCS (10.2 g, 76.2 mmol) was addedand the resulting mixture was stirred at 70° C. for 16 h. The mixturewas allowed to cool to room temperature and poured into cold brine. Theprecipitate was collected by filtration, rinsed with water and dried toafford the desired product as a white solid (14.6 g, 75% yield). ESI-MSm/z: 269.8 [M+H]⁺.

7-Bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione

A mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (23.3 g, 110mmol) and urea (68 g, 1100 mmol) was stirred at 200° C. for 4 h. Themixture was allowed to cool to room temperature. The solid was rinsedwith boiling water 3 times, collected by filtration and dried to affordthe desired product (24 g, 74% yield) as a gray solid.

7-Bromo-2,4,6-trichloro-8-fluoroquinazoline

The mixture of 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (14g, 48 mmol) in POCl₃ (200 mL) and DIPEA (20 mL) was stirred at refluxfor 16 h. The mixture was allowed to cool to room temperature and thenconcentrated in vacuo to remove POCl₃. The residue was purified by flashchromatography on silica gel (2% ethyl acetate/petroleum ether) and thenwashed with HCl (1M) to afford the product (9 g, 57% yield) as a yellowsolid.

tert-Butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (9 g, 27.3mmol) and Et₃N (11.4 mL, 82 mmol) in 1,4-dioxane (60 mL) at roomtemperature, the tert-butyl piperazine-1-carboxylate (5.07 g, 27.3 mmol)was added and the resulting mixture was stirred at 50° C. for 20 min.The mixture was allowed to cool to room temperature and partitionedbetween water and dichloromethane. The organic layer was washed with 1NHCl, water, saturated NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was triturated with a mixture ofpetroleum ether/ethyl acetate=5:1 to afford the desired product (12 g,91.5% yield) as a light yellow solid. ESI-MS m/z: 447.2 [M+H]⁺. ¹H-NMR(400 MHz, CDCl₃) δ: 7.76 (d, J=1.8 Hz, 1H), 3.90-3.87 (m, 4H), 3.67-3.64(m, 4H), 1.49 (s, 9H).

tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of compound tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(1 g, 2.1 mmol), 2-morpholinoethan-1-ol (1.4 g, 10.5 mmol) and KF (0.25g, 4.2 mmol) in dry DMSO (6 mL) was stirred at 120° C. for 3 h. Themixture was allowed to cool to RT, diluted with water and extracted withDCM. The organic layer was dried over Na₂CO₃, filtered and concentratedin vacuo. The residue was purified via Isolera One (EtOAc/Hexane=0-100%)to afford the desired product (675 mg, 56% yield).

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazine-1-carboxylate(835 mg, 1.0 eq.) in 1,4-dioxane (10 mL) in the sealed tube,(2-fluoro-6-hydroxyphenyl) boronic acid (1.16 g, 5.0 eq., 98%), tetrakis(842 mg, 0.5 eq.) and 5 mL of aqueous Na₂CO₃ (1 M) were added and theresulting mixture was stirred at 120° C. in the Microwave Reactor for 1h. Above procedure was repeated with another batch of4-(7-bromo-6-chloro-8-fluoro-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazine-1-carboxylate(647 mg, 1.0 eq.), (2-fluoro-6-hydroxyphenyl) boronic acid (899 mg, 5.0eq., 98%), tetrakis (653 mg, 0.5 eq.) in 5 mL of aqueous Na₂CO₃ (1 M)and 10 mL of dioxane in the sealed tube. These two batches of reactionmixture were combined, filtered and partitioned between EtOAc and water.The organic layer was dried with Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (DCM/MeOH=10:1) to afford the desired product (811 mg, 52% yield) asa solid. ESI-MS m/z: 606.2 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

2.5 mL of TFA was added into tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-morpholinoethoxy)quinazolin-4-yl)piperazine-1-carboxylate(811 mg, 1.0 eq.) in DCM (12 mL). The reaction mixture was stirred at RTfor 1 h. and was concentrated in vacuo.

The above obtained residue was suspended in aqueous Na₂CO₃ (1 M, 20 mL)and acetone (8 mL). Acryloyl chloride (268 μl, 2.1 eq.) was added. Afterstirring at RT for 2 h, the reaction mixture was concentrated in vacuoto remove acetone. The residue was taken in water, extracted with ethylacetate, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (DCM/MeOH=10:1) toafford the desired product (135 mg, 18% yield over two steps). ¹H NMR(500 MHz, DMSO-d6) δ: 10.23 (s, 1H), 7.95 (s, 1H), 7.34 (dd, J=15, 8.5Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.80 (m, 2H), 6.17 (dd, J=17, 2.5 Hz,1H), 5.74 (dd, J=10.5, 2.5 Hz, 1H), 4.46 (t, J=5.5 Hz, 2H), 3.90-3.76(m, 8H), 3.55 (t, J=5 Hz, 4H), 2.70 (t, J=5.5 Hz, 2H), 2.47 (m, 4H);ESI-MS m/z: 560.2 [M+H]⁺.

Example 21-(4-(6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 2 provides an exemplary preparation according to GeneralSynthetic Method B.

4-(7-bromo-6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a stirred mixture of tert-butyl4-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(5 g, 10.43 mmol) and 1-cyclopropylpiperidin-4-amine (4.4 g, 31.24 mmol)in i-PrOH (80 mL), DIPEA (3.4 g, 26.03 mmol) was added in one portion.The resulting mixture was stirred at reflux for 18 h. The mixture wasallowed to cool to room temperature, poured into water and extractedwith ethyl acetate (100 mL×2). The combined organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gel(dichloromethane:MeOH=150:1 to 20:1) to afford the desired product (6 g,98% yield).

tert-Butyl4-(6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate

tert-Butyl4-(7-bromo-6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(6 g, 10.28 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (5.4 g, 30.83mmol), Na₂CO₃ (3.3 g, 30.83 mmol), Pd(PPh₃)₄(1.2 g, 1.03 mmol) weresuspended in a mixture of dioxane (160 mL) and water (40 mL). Theresulting mixture was stirred at reflux for 16 h. The mixture wasallowed to cool to room temperature, poured into water, and thenextracted with ethyl acetate (150 mL×2). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM:MeOH=100:1 to 20:1)to afford the desired product (3.8 g, 54% yield).

1-(4-(6-Chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of tert-butyl4-(6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate(2.7 g, 4.26 mmol) in dichloromethane (40 mL), TFA (10 mL) was added andthe resulting mixture was stirred at room temperature for 1 h. Themixture was concentrated in vauco. The residue was dissolved indichloromethane (60 mL), treated with NaHCO₃, washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo to afford crudeproduct (2.0 g). The crude product was dissolved in dichloromethane (60mL) and cooled to −78° C. under a nitrogen atmosphere. To this mixture,TEA (1.1 g, 11.24 mmol) was added, followed by slow additional ofacryloyl chloride (481 mg, 5.34 mmol) in dichloromethane (30 mL) (over10 min). The resulting mixture was stirred at −78° C. for 15 min. Themixture was allowed to warm to room temperature, washed with NaHCO₃,dried over Na₂SO₄ and concentrated in vacuo. The residue was dissolvedin the mixture of THF and H₂O (4/1, 20 mL). Then LiOH.H₂O (1.0 g, 25mmol) was added and the mixture was stirred for 30 min. TLC showedcomplete conversion. The mixture was acidified with HCl (1N) to adjustpH=6-7 and then extracted with dichloromethane (50 mL×3). The combinedorganic layer was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (DCM/MeOH=100:1, 50:1, 20:1) toafford the pure product (800 mg, 36.4%) (Note: The temperature of rotaryevaporator water bath was controlled below 30° C.). 1H NMR (400 MHz,DMSO-d6) δ:13.15 (s, 1H), 7.80 (s, 1H), 7.57-7.55 (M, 2H), 7.38-7.36 (m,2H), 6.86 (dd, J=10.4, 16.4 Hz, 1H), 6.18 (dd, J=2, 16.4 Hz, 1H),5.77-5.73 (m, 1H), 3.84-3.70 (m, 9H), 2.92 (s, 2H), 2.26-2.20 (m, 2H),2.17 (s, 3H), 1.85-1.83 (m, 2H), 1.61-1.56 (m, 1H), 1.50-1.40 (m, 2H),0.40-0.28 (m, 4H). ESI-MS m/z: 589.3[M+H]⁺.

Example 31-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 3 provides another exemplary preparation according to GeneralSynthetic Method B.

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(504 mg, 1.0 eq.) in DMSO (20 mL), KF (308 mg, 5.0 eq.) and1-methylpiperidin-4-amine (192 μl, 1.4 eq.) were added and the resultingmixture was stirred at 120° C. for 1 h. The mixture was allowed to coolto RT, diluted with water and extracted with 20% isopropanol indichloromethane. The combined organic layer was dried with Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (DCM/MeOH=10:1) to afford thedesired product (614 mg, 100% yield) as a solid. ESI-MS m/z: 557.1[M+H]⁺.

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazine-1-carboxylate(362 mg, 1.0 eq.) in 1,4-dioxane (10 mL) in the sealed tube,(2-fluoro-6-hydroxyphenyl) boronic acid (476 mg, 5.0 eq., 98%), tetrakis(346 mg, 0.5 eq.) and aqueous Na₂CO₃ (1M, 5 mL) were added. The reactionmixture was stirred at 120° C. in the Microwave Reactor for 1 h. Aftercooling down, it was filtered and partitioned between EtOAc and water.The organic layer was dried with Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (DCM/MeOH=10:1) to afford the desired product (352 mg, 100% yield)as a solid. ESI-MS m/z: 589.3 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of above obtained tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazine-1-carboxylate(352 mg, 1.0 eq.) in dichloromethane (10 mL), TFA (2 mL) was added andthe resulting mixture was stirred at RT for 1 h. The mixture wasconcentrated in vacuo. The residue was dissolved in EtOAc, concentratedand dried in vacuo. The crude product was dissolved in DCM (10 mL) andcooled to −78° C. To this mixture, DIEA (1.04 mL, 10.0 eq.) and acryloylchloride (53 μL, 1.1 eq.) were added at −78° C. The reaction mixture wasstirred at −78° C. for 3 h. The mixture was warmed to RT, washed withNaHCO₃, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM/MeOH=10:1) toafford the desired product (40 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6)δ: 10.20 (s, 1H), 7.74 (s, 1H), 7.32 (dd, J=15, 8 Hz, 1H), 6.803 (m,3H), 6.166 (dd, J=16.5, 2 Hz, 1H), 5.74 (dd, J=10.5, 2 Hz, 1H), 4.03 (s,1H), 3.80-3.75 (m, 8H), 3.04 (s, 2H), 2.70 (s, 3H), 2.08 (m, 2H), 1.75(s, 2H); ESI-MS m/z: 543.2 [M+H]⁺.

Example 41-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 4 provides an exemplary preparation according to GeneralSynthetic Method C.

tert-butyl4-(7-Bromo-6-chloro-8-fluoro-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(1 g, 1.04 mmol), 2-(pyridin-2-yl)ethan-1-ol (1.28 g, 10.5 mmol) and KF(0.61 g, 10.5 mmol) in dry dioxane/DMSO (1:1, 10 mL) was stirred at 120°C. overnight. The mixture was allowed to cool to RT, diluted with EtOAcand washed with water. The organic layer was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (Isolera OneBiotage, EtOAc/Hexane=0-100%) to afford the desired product. Thematerial was used directly in the next step.

1-(4-(7-Bromo-6-chloro-8-fluoro-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The mixture of above obtained4-(7-bromo-6-chloro-8-fluoro-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazine-1-carboxylatein 50% of TFA in DCM (10 mL) was stirred at RT for 30 min. The mixturewas concentrated in vacuo. The residue was re-dissolved in DCM andwashed with sat. NaHCO₃. The organic layer was dried over Na₂SO₄ andfiltered. The mixture was concentrated in vacuo to reduce the solventvolume to 10 mL. To this mixture at 0° C., 0.3 mL of NEt3 was addedfollowed by acrylic chloride (190 mg, 2.1 mmol), and the resultingmixture was stirred at 0° C. for 1 h. The mixture was partitionedbetween water and DCM. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give crude product (0.6 g), which was used inthe next step without purification.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of above obtained1-(4-(7-bromo-6-chloro-8-fluoro-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(135 mg, 0.26 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (78.5 mg,0.39 mmol) and tetrakis (45 mg, 0.039 mmol) in co-solvent of dioxane (3mL) and 0.5 M Na₂CO₃ (1 mL) was stirred in a sealed tube in microwavereactor at 120° C. for 55 min. Additional amount of(2-fluoro-6-methoxyphenyl)boronic acid (78.5 mg, 0.39 mmol) and tetrakis(45 mg, 0.039 mmol) were added and the resulting mixture was stirred inmicrowave reactor at 120° C. for 55 min. The mixture was diluted withDCM and washed with water. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The above reaction at the same scale wasrepeated. The combined two batches were purified via Isolera One(MeOH/DCM=0-5%) to afford the desired product (120 mg, 82% yield).

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(2-(pyridin-2-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(120 mg, 0.21 mmol) in DCM (5 mL) at −78° C., BBr₃ (1.0 M, 2 mL) in DCMwas added and the resulting mixture was stirred from −78° C. to RT for 3h. To this mixture, i-PrOH (1 mL) was added and stirring was continuedfor 1 h. The mixture was partitioned between DCM and water. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified via Isolera One (MeOH/DCM=0-5%) to afford the desired product(59 mg, 50% yield) as a solid. ¹H NMR (500 MHz, CDCl₃) δ: 8.51 (d, J=4.0Hz, 1H), 7.94 (s, 1H), 7.73 (m, 1H), 7.31-7.39 (m, 2H), 7.24 (m, 1H),6.76-6.87 (m, 3H), 6.16 (d, J=16.5 Hz, 1H), 5.73 (d, J=10.5 Hz, 1H),4.74 (dd, J=6.5, 7.0 Hz, 2H), 3.7-3.9 (m, 8H), 3.23 (t, J=7.0 Hz, 2H);ESI-MS m/z: 553.2 [M+H]⁺.

Example 51-(4-(6-chloro-8-fluoro-2-((2-(2-methyl-1H-imidazol-1-yl)ethyl)amino)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 5 provides an exemplary preparation according to GeneralSynthetic Method D.

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-((2-(2-methyl-1H-imidazol-1-yl)ethyl)amino)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(240 mg, 0.5 mmol), 2-(2-methyl-1H-imidazol-1-yl)ethan-1-aminedihydrochloride (119 mg, 0.6 mmol) and DIEA (195 mg, 1.5 mmol) in MeOH(10 mL) in pressure vessel was stirred at 120° C. overnight. The mixturewas allowed to cool to RT and partitioned between DCM and water. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was used directly in the next step without further purification.

1-(4-(6-Chloro-8-fluoro-2-((2-(2-methyl-1H-imidazol-1-yl)ethyl)amino)-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-((2-(2-methyl-1H-imidazol-1-yl)ethyl)amino)quinazolin-4-yl)piperazine-1-carboxylateusing (5-methyl-1H-indazol-4-yl)boronic acid instead of(2-fluoro-6-methoxyphenyl)boronic acid in the Suzuki coupling stepaccording to the procedure described in Example 4. ¹H NMR (500 MHz,CDCl₃) δ: 13.14 (s, 1H), 7.82 (s, 1H), 7.55-7.58 (m, 2H), 7.37 (d, J=9.0Hz, 1H), 7.02 (s, 1H), 6.85 (dd, J=10.5, 16.5 Hz, 1H), 6.67 (s, 1H),6.18 (d, J=16.5 Hz, 1H), 5.74 (d, J=10.5 Hz, 1H), 4.08 (br s, 2H),3.53-3.87 (m, 10H), 2.26 (s, 3H), 2.17 (s, 3H); ESI-MS m/z: 575.2[M+H]⁺.

Example 61-(4-(6-chloro-2-(2-(dimethylamino)ethyl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 6 provides an exemplary preparation according to GeneralSynthetic Method E.

7-Bromo-6-chloro-2-(2-chloroethyl)-8-fluoroquinazolin-4-ol

A mixture of methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (500 mg,1.77 mmol) and 3-methoxypropanenitrile (1.1 g, 12.94 mmol) in dioxane(30 mL) was blown with HCl gas for 50 min at R.T. The mixture wasstirred at 80° C. for 16 h. The mixture was allowed to cool to RT,poured into water (200 mL), and extracted with ethyl acetate (50 mL×3).The combined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatography(DCM/MeOH=20:1) to afford the product as a faint yellow solid (58 mg,10% yield). ESI-MS m/z: 339.9 [M+H]⁺.

7-Bromo-4,6-dichloro-8-fluoro-2-vinylquinazoline

The mixture of7-bromo-6-chloro-2-(2-chloroethyl)-8-fluoroquinazolin-4-ol (350 mg, 1.03mmol) and DIEA (3 mL) in POCl₃ (30 mL) was stirred at 130° C. for 2 h.The mixture was evaporated under reduced pressure. The residue was addedto a dichloromethane-Et₃N solution. The resulting mixture was pouredinto 1M HCl (150 mL) solution. The aqueous phase was extracted with DCM(30 mL×2). The organic layer was dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography on silica gel(ethyl acetate/Petroleum ether=1:10) to afford the product (120 mg, 36%yield) as a yellow solid. ESI-MS m/z: 322.9 [M+H]⁺.

tert-Butyl-4-(7-bromo-6-chloro-8-fluoro-2-vinylquinazolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-4,6-dichloro-8-fluoro-2-vinylquinazoline (120 mg,0.373 mmol), tert-butyl piperazine-1-carboxylate (84 mg, 0.447 mmol) andEt₃N (38 mg, 0.373 mmol) in dioxane (20 mL) was stirred at 50° C. for1.5 h. The mixture was extracted with ethyl acetate. The organic layerwas washed with Sat. NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (ethyl acetate/Petroleum ether=1:5) to afford the product(110 mg, 63% yield) as an orange oil. ESI-MS m/z: 473.1[M+H]⁺.

tert-Butyl-4-(7-bromo-6-chloro-2-(2-(dimethylamino)ethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a mixture oftert-butyl-4-(7-bromo-6-chloro-8-fluoro-2-vinylquinazolin-4-yl)piperazine-1-carboxylate(110 mg, 0.23 mmol) in dimethylamine (2.0 M in THF) AcOH (5 drops) wasadded and the resulting mixture was stirred at 60° C. for 3 h. Themixture was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel (MeOH/DCM=1:10) to afford thedesired product (82 mg, 69% yield) as a brown solid. ESI-MS m/z: 516.2[M+H]⁺.

tert-butyl-4-(6-chloro-2-(2-(dimethylamino)ethyl)-8-fluoro-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-2-(2-(dimethylamino)ethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(82 mg, 0.16 mmol),(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (165mg, 0.64 mmol), Pd(PPh₃)₄ (28 mg, 0.024 mmol) and Na₂CO₃ (51 mg, 0.48mmol) in 1,4-dioxane/H₂O (15 mL/5 mL) was stirred at 110° C. under argonfor 16 h. The mixture was allowed to cool to RT and extracted with ethylacetate (50 mL). The organic layer was washed with 2 M NaOH solution,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (DCM/MeOH=20:1 to10:1) to afford the desired product (37 mg, 36% yield) as an orangecolor oil. ESI-MS m/z: 652.4 [M+H]⁺.

1-(4-(6-Chloro-2-(2-(dimethylamino)ethyl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture oftert-butyl-4-(6-chloro-2-(2-(dimethylamino)ethyl)-8-fluoro-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate(37 mg, 0.057 mmol) in 10 mL of 20% TFA-DCM solution was stirred for 16h. The mixture was concentrated in vacuo.

To a solution of above obtained residue in DCM (20 mL) and Et₃N (58 mg,0.57 mmol) at −40° C., acryloyl chloride (5 mg, 0.057 mmol) in DCM (1mL) was added dropwise and the resulting mixture was stirred for 10 min.The mixture was quenched with 20 mL of saturated NaHCO₃ solution. Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified through Al₂O₃chromatography followed by Pre-HPLC purification to afford the desiredproduct. ESI-MS m/z: 523.3 [M+H]⁺.

Example 71-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 7 provides an exemplary preparation according to GeneralSynthetic Method F.

tert-Butyl-4-(2-(acetoxymethyl)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl-4-(7-bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(2.25 g, 4.56 mmol) and NaOAc (1.12 g, 13.69 mmol) in DMSO (70 mL) wasstirred at 80° C. for 16 h. The mixture was allowed to cool to RT,poured into water (150 mL) and extracted with ethyl acetate (30 mL×4).The organic layer was washed with Sat. NaHCO₃ and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether=1:5 to 1:3)to afford the desired product (1.27 g, 53% yield) as a yellow solid.ESI-MS m/z: 519.2 [M+H]⁺.

tert-Butyl-4-(7-bromo-6-chloro-8-fluoro-2-(hydroxymethyl)quinazolin-4-yl)piperazine-1-carboxylate

To a mixture oftert-butyl-4-(2-(acetoxymethyl)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(1.27 g, 2.45 mmol) in THF (50 mL), LiOH.H₂O (412 mg, 9.81 mmol) inwater (40 mL) was added and the resulting mixture was stirred at RT for2 h. The mixture was diluted with brine (100 mL) and extracted withethyl acetate (50 mL×3). The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (ethyl acetate/petroleum ether=1:5to 1:2) to afford the desired product (969 mg, 83% yield) as a yellowsolid. ESI-MS m/z: 477.1 [M+H]⁺.

tert-Butyl-4-(7-bromo-6-chloro-8-fluoro-2-formylquinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl-4-(7-bromo-6-chloro-8-fluoro-2-(hydroxymethyl)quinazolin-4-yl)piperazine-1-carboxylate(969 mg, 2.04 mmol) in dichloromethane (110 mL) MnO₂ (1.77 g, 20.38mmol) was added and the resulting mixture was stirred at 80° C. for 16h. The mixture allowed to cool to RT and filtered through silicachromatography and concentrated in vacuo to afford the desired product(892 mg, 92% yield) as a yellow solid.

7-Bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fuoroquinazoline-2-carboxylicAcid

A mixture oftert-butyl-4-(7-bromo-6-chloro-8-fluoro-2-formylquinazolin-4-yl)piperazine-1-carboxylate (892 mg, 1.88 mmol) in a mixture of THF (30mL), dichloromethane (10 mL), t-BuOH (30 mL) and H₂O (30 mL) at 0° C.,NaClO₂ (682 mg, 7.54 mmol), NaH₂PO₄ (904 mg, 7.54 mmol), and2-methylbut-2-ene (923 mg, 13.19 mmol) were added and the resultingmixture was stirred for 2 h. The mixture was evaporated under reducedpressure. The residue was diluted with 50 mL of water and 100 mL ofethyl acetate, and then adjusted pH to 3 with 1M HCl. The mixture wasextracted with ethyl acetate (30 mL×3). The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afford thecrude product (1.35 g) as a yellow solid. ESI-MS m/z: 489.3 [M+H]⁺. Thecrude product was used directly in the next step.

4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline-2-carboxylicAcid

A mixture of7-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fluoroquinazoline-2-carboxylicacid (800 mg, 1.63 mmol) and (2-fluoro-6-methoxyphenyl)boronic acid (832mg, 4.90 mmol), Na₂CO₃ (692 mg, 6.54 mmol) in dioxane (40 mL) and H₂O(10 mL) was stirred at 100° C. under argon for 5 h. The mixture wasdiluted with ethyl acetate (60 mL), added 50 mL 0.5 M HCl, and thenextracted with ethyl acetate (30 mL×2). The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afford theproduct (725 mg, 83% yield) as a yellow solid. ESI-MS m/z: 535.3 [M+H]⁺.

tert-Butyl-4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of4-(4-(tert-butoxycarbonyl)piperaziCn-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline-2-carboxylicacid (200 mg, 0.37 mmol), morpholine (81 mg, 0.94 mmol) and BOP (248 mg,0.56 mmol) in DMF (20 mL), DIEA (193 mg, 1.496 mmol) was added and theresulting mixture was stirred at RT for 2 h. The mixture was quenchedwith water and extracted with ethyl acetate (30 mL×3). The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (ethylacetate/petroleum ether=1:2 to 1:1 and dichloromethane/MeOH=40:1) toafford the desired product (213 mg, 94% yield) as a white solid. ESI-MSm/z: 604.4 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazine-1-carboxylate(213 mg, 0.33 mmol) in MeOH.HCl (20 mL, 2.8 M) solution was stirred for2 h. The mixture was concentrated in vacuo. The residue was dissolved inDCM (30 mL) and Et₃N (178 mg, 1.76 mmol). The mixture was cooled to 0°C. and acryloyl chloride (48 mg, 0.33 mmol) in DCM (1 mL) was addeddropwise. The resulting mixture was stirred for 10 min, and quenched by20 mL saturated NaHCO₃ solution. The organic layer was separated, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM/MeOH=30:1) toafford the desired product (169 mg, 85% yield) as a yellow solid. ESI-MSm/z: 558.3 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-(morpholine-4-carbonyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(169 mg, 0.30 mmol) in DCM (30 mL) at −78° C. under nitrogen, BBr₃ (265mg, 1.06 mmol) was added and the resulting mixture was stirred at RT for1 h and at 30° C. for 1 h. The mixture was quenched with NaHCO₃ solutionat −30° C., and then extracted with 10% MeOH-DCM co-solvent. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM/MeOH=30:1) followed by pre-TLC plate purification to afford thedesired product (25 mg, 18% yield) as a white solid. 1H NMR (400 MHz,DMSO-d6) δ: 10.35 (s, 1H), 8.08 (s, 1H), 7.41 (dd, J=8.4, 15.6 Hz, 1H),6.88 (m, 3H), 6.20 (dd, J=2.4, 16.8 Hz, 1H), 5.76 (dd, J=2.4, 10.0 Hz,1H), 3.98 (m, 16H); ESI-MS m/z: 454.3 [M+H]⁺.

Example 84-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazoline-2-carbonitrile

Example 8 provides an exemplary preparation according to GeneralSynthetic Method G.

tert-Butyl-4-(2-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a mixture of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline-2-carboxylicacid (525 mg, 0.98 mmol) and NH₄Cl (131 mg, 2.45 mmol), BOP (651 mg,1.47 mmol) in DMF (20 mL), DIEA (633 mg, 4.91 mmol) was added and theresulting mixture was stirred at RT for 2 h. The mixture was quenchedwith water and extracted with ethyl acetate (30 mL×3). The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (DCM/MeOH=40:1to 30:1) to afford the desired product (288 mg, 55% yield) as a whitesolid. ESI-MS m/z: 604.4 [M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazoline-2-carboxamide

The title compound was prepared from tert-butyl4-(2-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylateaccording to the procedure described in Example 7.1H NMR (400 MHz,DMSO-d6) δ: 10.34 (s, 1H), 8.13 (m, 2H), 7.79 (s, 1H), 7.39 (t, J₁=8.4Hz, J₂=15.6 Hz, 1H), 6.89-6.81 (m, 3H), 6.20 (dd, J₁=2.0 Hz, J₂=16.4 Hz,1H), 5.77 (dd, J₁=2.4 Hz, J₂=10.8 Hz, 1H), 4.04 (m, 4H), 3.84 (m, 4H);ESI-MS m/z: 474.3 [M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazoline-2-carbonitrile

To a mixture of4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazoline-2-carboxamide(70 mg, 0.15 mmol) in DCM (30 mL) and Et₃N (2 mL), (CF₃CO)₂O (0.5 mL)was added and the resulting mixture was stirred at RT for 20 min. Themixture was quenched with saturated NaHCO₃ aqueous solution (70 mL) andextracted with DCM (30 mL×2). The organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromatography (dichloromethane/ethyl acetate=1:1) to afford the productas a white solid (24 mg, 36% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.43(s, 1H), 8.15 (s, 1H), 7.42 (m, 1H), 6.89 (m, 3H), 6.21 (m, 1H), 5.76(m, 1H), 4.06 (m, 8H); ESI-MS m/z: 456.3 [M+H]⁺.

Example 91-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-(pyrimidin-2-ylamino)ethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 9 provides an exemplary preparation according to GeneralSynthetic Method H.

3-Amino-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylic Acid

To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (10 g, 43mmol) in 1,4-dioxane (400 mL) and water (100 mL),2-fluoro-6-methoxyphenylboronic acid (36 g, 213 mmol),tetrakis(triphenylphosphine)palladium (2.5 g, 2.15 mmol) and Na₂CO₃ (27g, 258 mmol) were added. The mixture was degassed and back-filled withnitrogen several times, and then stirred at 100° C. overnight. Themixture was allowed to cool to RT and partitioned between water ethylacetate. The organic layer was discarded, and 1M HCl solution was addedto aqueous phase to adjust pH<3. The aqueous phase was extracted withethyl acetate (200 mL×2), washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (11 g, 92% yield) asa white solid. ESI-MS m/z: 280.1 [M+H]⁺.

3-Amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicAcid

To a solution of3-amino-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylic acid (11g, 39.6 mmol) in N,N-dimethylformamide (100 mL) at RT,N-chlorosuccinimide (5.27 g, 39.6 mmol) was added and the resultingmixture was stirred at 100° C. for 1 h. The mixture was allowed to coolto RT, and then slowly added to H₂O (300 mL). The mixture was filteredand the cake was dried to afford the desired product (11.5 g, 93.1%yield) as a brown solid.

6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline-2,4-diol

A mixture of methyl3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicacid (11.5 g, 37 mmol) and urea (22.5 g, 370 mmol) was stirred at 210°C. for 3 h. The mixture was allowed to cool to RT and diluted with water(300 mL). The mixture was filtered and the cake was dried to afford thedesired product (10 g, 80% yield) as a brown solid.

2,4,6-Trichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

The mixture of6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline-2,4-diol (10g, 29.7 mmol) in POCl₃ (200 mL) and DIPEA (20 mL) was stirred at refluxfor 16 h. The mixture was allowed to cool to RT and concentrated invacuo to remove POCl₃. The residue was purified by flash chromatographyon silica gel (30% ethyl acetate/petroleum ether) to afford the product(6.8 g, 61.5% yield) as a brown solid.

tert-Butyl4-(2,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of2,4,6-trichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline (6.8 g,18.2 mmol) and DIEA (2.82 g, 21.8 mmol) in 1,4-dioxane (100 mL) at RT,tert-butyl piperazine-1-carboxylate (3.39 g, 18.2 mmol) was added andthe resulting mixture was stirred at RT for 2 h. The mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=0-50%) to afford the desired product (9 g, 94%yield) as a yellow solid. ESI-MS m/z: 524.1 [M+H]⁺.

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-vinylquinazolin-4-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl 4-(2,6-dichloro-8-fluoro-7-(2-fluoro-6-meth oxyphenyl)quinazolin-4-yl) piperazine-1-carboxylate(3.14 g, 6 mmol) in THF (100 mL),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.85 g, 12 mmol),palladium(II)bis(triphenylphosphine)dichloride (420 mg, 0.598 mmol) andK₃PO_(4.)3H₂O (27 g, 258 mmol) were added. The mixture was flushed withnitrogen several times, and then stirred at 80° C. overnight. Themixture was allowed to cool to RT, diluted with water (50 mL), andextracted with ethyl acetate (20 mL×3). The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=0-50%) afford the desired product (2.5 g, 81%yield) as a yellow solid. ESI-MS m/z: 517.1 [M+H]⁺.

tert-Butyl4-(6-chloro-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-vinylquinazolin-4-yl)piperazine-1-carboxylate(2.5 g, 4.84 mmol) and (2,4-dimeth-oxyphenyl)methanamine (1.62 g, 9.68mmol) in ethanol (20 mL) and acetic acid (2 mL) was stirred at refluxfor 48 h. The mixture was allowed to cool to RT and concentrated invacuo to remove ethanol. NaHCO₃ solution was added to adjust pH>7, andthen extracted with ethyl acetate (30 mL×3). After evaporation of thecombined organic layer, the residue was purified by flash chromatographyon silica gel (7M NH₃ in CH₃OH/DCM=0-10%) to afford the desired product(800 mg, 24% yield) as a white solid. ESI-MS m/z: 684 [M+H]⁺.

tert-Butyl4-(6-chloro-2-(2-((2,4-dimethoxybenzyl)(pyrimidin-2-yl)amino)ethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a stirred solution of4-(6-chloro-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(300 mg, 0.44 mmol) in DMSO (15 mL), KF (76 mg, 1.32 mmol) and2-chloropyrimidine (100 mg, 0.88 mmol) were added and the resultingmixture was stirred at 80° C. overnight. The mixture was allowed to coolto RT, diluted with water (50 mL) and extracted with ethyl acetate (30mL×2). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (MeOH/DCM=0-5%) to afford thedesired product (310 mg, 92.6% yield) as a yellow solid. ESI-MS m/z:762.1 [M+H]⁺.

N-(2-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)ethyl)pyrimidin-2-amine

The mixture of tert-butyl4-(6-chloro-2-(2-((2,4-dimethoxybenzyl)(pyrimidin-2-yl)amino)ethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(310 mg, 0.41 mmol) in 2,2,2-trifluoroacetic acid (10 mL) was stirred atRT for 2 h and then concentrated in vacuo. The residue was basified withNaHCO₃ solution to adjust pH>7, and then extracted with ethyl acetate(30 mL×3). After evaporation of the combined organic layer, the desiredproduct was obtained (200 mg, 74% yield) as a yellow solid. ESI-MS m/z:662.1 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(2-(pyrimidin-2-ylamino)ethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared fromN-(2-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)ethyl)pyrimidin-2-amineaccording to the procedure described in Example 7. ¹H NMR (400 MHz,DMSO-d6) δ: 10.28 (s, 1H), 8.25-8.24 (d, 2H), 7.99 (s, 1H), 7.38-7.36(m, 1H), 7.20-7.17 (m, 1H), 6.88-6.80 (m, 3H), 6.55-6.53 (m, 1H),6.20-6.16 (dd, J=1.6, 18.4 Hz, 1H), 5.16-5.13 (dd, J=1.2, 12.0 Hz, 1H),3.88-3.76 (m, 10H), 3.10-3.06 (m, 2H). ESI-MS m/z: 552.1 [M+H]⁺.

Example 101-(4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,8-dimethoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 10 provides an exemplary preparation according to GeneralSynthetic Method J.

tert-Butyl4-(7-bromo-6-chloro-2,8-dimethoxyquinazolin-4-yl)piperazine-1-carboxylate

tert-Butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(240 mg, 0.5 mmol) in a flask was dried under high vacuum overnight. NaHwas added and the mixture was cooled down to −78° C., then THF (2 mL,cooled to −78° C.) was added. The reaction mixture was slowly warmed upto RT in 2 h, and then was frozen at −78° C. overnight. The reaction wasquenched with THF/water and further diluted with EtOAc (100 mL). Theorganic layer was separated, washed with water and brine, dried withNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (1-4% MeOH in DCM) to afford thedesired product (221 mg, 91% yield). ESI-MS m/z: 487.1 [M+H]⁺.

2-(6-Chloro-2,8-dimethoxy-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenol

A solution of tert-butyl4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,8-dimethoxyquinazolin-4-yl)piperazine-1-carboxylate(117 mg, 0.27 mmol) in DCM (2 mL) and TFA (2 mL) was stirred for 10 minat RT. The mixture was concentrated in vacuo and the residue obtained2-(6-chloro-2,8-dimethoxy-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenolwas used directly in the next step.

1-(4-(6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-2,8-dimethoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of2-(6-chloro-2,8-dimethoxy-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenol(supposedly 0.226 mmol) in 4 mL of methyl-THF and 2 mL of water, NaHCO₃solid (190 mg, 2.26 mmol, 10 eq.) was slowly added and the resultingmixture was stirred for 5 min. Then acryloyl chloride was added and thereaction was stirred at RT for 0.5 h. The mixture was treated with NaOHaq (1N, 2 mL) for 5 min. The organic layer was separated from waterlayer and the water layer was further extracted with EtOAc (10 mL×3).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (0-7% MeOH in DCM) to afford the desired product (88.4 mg,83%). ¹H NMR (500 MHz, CDCl₃) δ: 7.72 (s, 1H), 7.31 (m, 1H), 6.86 (d,J=8.0 Hz, 1H), 6.80 (t, J=9.0 Hz, 1H), 6.60 (dd, J=17, 10.5 Hz, 1H),6.37 (dd, J=17, 1.5 Hz, 1H), 5.78 (m, 2H), 4.08 (s, 3H), 4.03 (s, 3H);ESI-MS m/z: 473.1 [M+H]⁺.

Example 111-(4-(6-chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 11 provides an exemplary preparation according to GeneralSynthetic Method K.

tert-Butyl4-(6-chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

tert-Butyl4-(2,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(400 mg, 0.76 mmol), 1-(azetidin-3-yl)-4-cyclopropylpiperazine (207 mg,1.14 mmol) and DIEA (186 mg, 1.53 mmol) were dissolved in i-PrOH (20mL). The solution was stirred at 100° C. for 16 h. It was allowed tocool to RT and partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (MeOH/dichloromethane=0-5%) to afford the desired product (300 mg,58.7% yield) as a yellow solid. ESI-MS m/z: 670.5 [M+H]⁺.

1-(4-(6-Chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The mixture of tert-butyl4-(6-chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(300 mg, 0.45 mmol) in 2,2,2-trifluoroacetic acid (10 mL) was stirred atRT for 2 h. The mixture was concentrated in vacuo to remove2,2,2-trifluoroacetic acid. NaHCO₃ solution was added to adjust pH>7,and then extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ aqueous solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in DCM (10 mL), Et₃N(68 mg, 0.38 mmol) was added and the resulting solution was cooled to 0°C. Acryloyl chloride (50 mg, 0.54 mmol) was added to the mixture. Theresulting mixture was stirred at RT for 0.5 h, poured into water andthen extracted with dichloromethane. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1-2%methanol/dichloromethane) to afford the desired product (220 mg, 78.7%yield) as a yellow solid. ESI-MS m/z: 624.3 [M+H]⁺.

1-(4-(6-Chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-2-(3-(4-cyclopropylpiperazin-1-yl)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(220 mg, 0.35 mmol) in dichloromethane (40 mL) at −78° C., BBr₃ (883 mg,3.53 mmol) was added. The resulting solution was allowed to warm to RTand stirred at RT for 4 h. The mixture was cooled to −40° C., quenchedwith NaHCO₃, and extracted with DCM (30 mL×3). The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (MeOH/dichloromethane=0-5%) to afford the desired product (55 mg,25.6% yield) as a yellow solid. ESI-MS m/z: 610.3 [M+H]⁺; ¹HNMR (400MHz, DMSO-d6) δ: 10.20 (s, 1H), 7.77 (s, 1H), 7.36-7.30 (m, 1H),6.87-6.77 (m, 3H), 6.20-6.15 (dd, J=2, 16.8 Hz, 1H), 5.75-5.72 (dd,J=2.4, 10.8 Hz, 1H), 4.13-4.09 (m, 2H), 3.92-3.75 (m, 8H), 3.36-3.34 (m,2H), 3.19-3.16 (m, 1H), 2.55-2.31 (m, 8H), 1.60-1.57 (m, 1H), 0.40-0.38(m, 2H), 0.28-0.27 (m, 2H).

Example 121-(4-(6-chloro-2-((1-cyclopropylpiperidin-4-yl)methoxy)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 12 provides an exemplary procedure according to Method L

tert-butyl4-(2-((1-cyclopropylpiperidin-4-yl)methoxy)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of (1-cyclopropylpiperidin-4-yl)methanol (258 mg, 1.67mmol) in DMF (20 mL) at 0° C., NaH (67 mg, 1.67 mmol, 60% in oil) wasadded. The mixture was stirred at 0° C. for 30 min, tert-butyl4-(2,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(400 mg, 0.83 mmol) was added and the resulting mixture was stirred atRT for 16 h. This mixture was quenched with saturated NH₄Cl solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (5-10%methanol/dichloroethane) to afford the desired product (150 mg, 28%yield).

1-(4-(2-((1-Cyclopropylpiperidin-4-yl)methoxy)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of tert-butyl4-(2-((1-cyclopropylpiperidin-4-yl)methoxy)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylat(150 mg, 0.28 mmol) in dichloromethane (5 mL), TFA (2.5 mL) was addedand the resulting mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo. The residue was added to the mixture of Et₃N(83.6 mg, 0.83 mmol) in dichloromethane (10 mL). The mixture was stirredfor 5 min and then acryloyl chloride (25 mg, 0.28 mmol) was added. Theresulting mixture was stirred at RT for 0.5 h, poured into water andthen extracted with dichloromethane. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1-2%methanol/dichloromethane) to afford the desired product (100 mg, 61%yield).

1-(4-(2-((1-Cyclopropylpiperidin-4-yl)methoxy)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(2-((1-cyclopropylpiperidin-4-yl)methoxy)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(100 mg, 0.167 mmol) in dichloromethane (10 mL) at −78° C., BBr₃ (418mg, 1.67 mmol) was added and the resulting mixture was stirred at RT for1 h. This mixture was quenched with saturated NaHCO₃ and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃aqueous solution and brine, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(5-10% methanol/dichloroethane) to afford the desired product (28 mg,29% yield) as a solid. ESI-MS m/z: 584.3 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d6) δ: 10.28 (s, 1H), 7.95 (s, 1H), 7.36 (m, 1H), 6.87-6.79 (m,3H), 6.20-6.16 (dd, J=2.4, 16.8 Hz, 1H), 5.77-5.73 (dd, J=2.1, 10.0 Hz,1H), 4.20 (m, 2H), 3.89-3.76 (m, 8H), 2.97 (m, 2H), 2.19 (m, 1H), 1.70(m, 2H), 1.60 (m, 1H), 1.24-1.16 (m, 4H), 0.41 (m, 2H), 0.28 (m, 2H).

Example 131-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 13 provides an exemplary procedure according to Method M

Methyl3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylate

3-Amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicacid (2 g, 6.41 mmol) and K₂CO₃ (1.33 g, 9.62 mmol) were dissolved inDMF (20 mL), CH₃I (0.994 g, 7.05 mmol) was added and the resultingmixture was stirred at RT for 2 h. The mixture was partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (petroleum ether/ethyl acetate=3:1)to afford the desire product (1.9 g, 90.3% yield) as an off-white solid.ESI-MS m/z: 328.0 [M+H]⁺.

6-Chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol

Methyl3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylate(1.85 g, 5.67 mmol) and 2-chloroacetonitrile (2.2 g, 28.37 mmol) weredissolved in 1,4-dioxane (80 mL), HCl gas was vapored into the solutionfor 30 min. The resulting mixture was stirred at 100° C. for 16 h. Themixture was partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum ether/ethyl acetate=3:1) to afford the desire product(1.85 g, 88.5% yield) as an off-white solid. ESI-MS m/z: 371.1 [M+H]⁺.

4,6-Dichloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

6-Chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol(1.9 g, 5.14 mmol) was dissolved in POCl₃ (40 mL), DIPEA (4 mL) wasadded and the resulting mixture was stirred at 110° C. for 16 h. Themixture was concentrated in vacuo and the residue was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (petroleumether/ethyl acetate=4:1) to afford the desire product (1.1 g, 55.3%yield) as an off-white solid.

tert-Butyl4-(6-chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A solution of4,6-dichloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline(1.1 g, 2.84 mmol) and tert-butyl piperazine-1-carboxylate (791 mg, 4.25mmol) in isopropanol (100 mL) was stirred at 80° C. for 2 h. The mixturewas partitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=0-50%) to afford the desired product (650 mg,42.6% yield) as a yellow solid.

tert-Butyl4-(2-(azidomethyl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(6-chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(650 mg, 1.21 mmol) in DMSO (10 mL), NaN₃ (118 mg, 1.81 mmol) was addedand the resulting mixture was stirred at 60° C. for 1 h. The mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(petroleum ether/ethyl acetate=3:1) to afford the desire product (600mg, 90.1% yield) as an off-white solid.

tert-Butyl4-(2-(aminomethyl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

4-(2-(Azidomethyl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(600 mg, 1.09 mmol) and PPh₃ (574 mg, 2.18 mmol) were dissolved in THF(10 mL) and H₂O (10 mL), and the resulting mixture was stirred at RT for16 h. The mixture was concentrated in vacuo and the residue was purifiedby flash column chromatography on silica gel (petroleum ether/ethylacetate=3:1) to give a crude desired product (600 mg). ESI-MS m/z: 520.7[M+H]⁺.

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(2-(aminomethyl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(600 mg, 1.15 mmol), pyridine N-oxide (120 mg, 1.26 mmol) and Py-BrOP(804 mg, 1.73 mmol), DIEA (445 mg, 3.45 mmol) was added and theresulting mixture was stirred at RT for 2 h. The mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (petroleumether/ethyl acetate=3:1) to afford the desire product (450 mg, 66.1%yield) as an off-white solid. ESI-MS m/z: 597.3 [M+H]⁺.

N-((6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)methyl)pyridin-2-amine

4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazine-1-carboxylate(450 mg, 0.76 mmol) was dissolved in 2,2,2-trifluoroacetic acid (10 mL).The resulting mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo to remove TFA. NaHCO₃ solution was added to adjustpH>7, and then extracted with ethyl acetate. The organic layer wasconcentrated in vacuo to afford the desired product (330 mg, 87.8%yield) as a yellow solid.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

N-((6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)methyl)pyridin-2-amine(330 mg, 0.667 mmol) and Et₃N (80.8 mg, 0.801 mmol) were dissolved indichloromethane (20 mL) and cooled to −78° C., acryloyl chloride (61 mg,0.337 mmol) was added into the solution. The resulting mixture wasstirred at RT for 10 min, NaHCO₃ solution was added to adjust pH>7, andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (dichloromethane/MeOH=30:1) toafford the desired product (220 mg, 60% yield) as an off-white solid.ESI-MS m/z: 551.6 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-((pyridin-2-ylamino)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(220 mg, 0.4 mmol) was dissolved in dichloromethane (20 mL) and themixture was cooled to −78° C., BBr₃ (1.0 g, 4 mmol) was added drop wiseinto the solution. The resulting mixture was allowed to warm to RT andstirred at RT for 4 h. The mixture was cooled to −30° C. and NaHCO₃solution was added to adjust pH>7, and then extracted withdichloromethane. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography on silica gel (dichloromethane/MeOH=30:1) followed byPre-HPLC to afford the desire product (40 mg, 18.7% yield) as anoff-white solid. ESI-MS m/z: 537.7 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d6) δ:10.30 (s, 1H), 8.00 (s, 1H), 7.93-7.92 (m, 1H), 7.40-7.35 (m, 2H),6.90-6.80 (m, 4H), 6.66-6.64 (m, 1H), 6.50-6.47 (m, 1H), 6.20-6.15 (m,1H), 5.76-5.73 (m, 1H), 4.61-4.59 (m, 2H), 3.87-3.68 (m, 8H).

Example 141-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 14 provides an exemplary procedure according to Method O.

7-Bromo-6-chloro-8-fluoro-2-(trifluoromethyl)quinazolin-4(1H)-one

The mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2.0 g,7.49 mmol) and 2,2,2-trifluoroacetamide (2.54 g, 22.5 mmol) was stirredat 150° C. for 48 h. The mixture was extracted with EtOAc (150 mL). Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (50% ethyl acetate/petroleum ether) to afford the desiredproduct (500 mg, 19% yield).

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of7-bromo-6-chloro-8-fluoro-2-(trifluoromethyl)quinazolin-4(1H)-one (500mg, 1.45 mmol), tert-butylpiperazine-1-carboxylate (537 mg, 2.89 mmol),triethylamine (439 mg, 4.35 mmol) andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.5g, 2.89 mmol) in THF (15 mL) was stirred at 50° C. for 16 h. The mixturewas extracted with EtOAc (150 mL). The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (50% ethylacetate/petroleum ether) to afford the desired product (600 mg, 81%yield). ESI-MS m/z: 513.3[M+H]⁺.

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate(250 mg, 0.48 mmol), 2-fluoro-6-hydroxyphenylboronic acid (449 mg, 2.91mmol), Pd(PPh₃)₄(56 mg, 0.048 mmol) and Na₂CO₃ (257 mg, 2.43 mmol) in1,4-dioxane/H₂O (10 mL/2 mL) was stirred at 100° C. for 16 h underargon. The mixture was allowed to cool to RT and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(dichloromethane/methanol=100:1) to yield the desired product (130 mg,49% yield) as an off-white solid. ESI-MS m/z: 545.2 [M+H]⁺.

2-(6-Chloro-8-fluoro-2-(trifluoromethyl)-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenol

To a solution of tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate(130 mg, 0.24 mmol) in dichloromethane (5 mL) at RT, TFA (1 mL) wasadded and the resulting mixture was stirred at RT for 1 h. The mixturewas concentrated in vacuo. The residue was partitioned between NaHCO₃solution and ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo to afford the desiredproduct (100 mg, 100% yield).

2-(4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fuoro-2-(trifluoromethyl)quinazolin-7-yl)-3-fluorophenylAcrylate

To a solution of above obtained crude2-(6-chloro-8-fluoro-2-(trifluoromethyl)-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenol(100 mg, 0.238 mmol) in Et₃N (72 mg, 0.71 mmol) and dichloromethane (10mL) at 0° C., acryloyl chloride (32 mg, 0.35 mmol) was added and theresulting mixture was stirred at 0° C. for 2 h. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution, and extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃solution and brine, dried over Na₂SO₄ and concentrated in vacuo toafford crude product (50 mg) which was used in the next step directly.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

2-(4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-2-(trifluoromethyl)quinazolin-7-yl)-3-fluorophenylacrylate (50 mg, 0.09 mmol) was dissolved in a mixture of THF (5 mL) andH₂O (2.5 mL). LiOH.H₂O (37 mg, 0.92 mmol) was added and the mixture wasstirred at RT for 2 h. The mixture was poured into water and extractedwith EtOAc. The organic layer was washed with water and brine, driedover Na₂SO₄, concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (1-5% MeOH/dichoromethane) to affordthe desired product (30 mg, 65% yield) as a white solid. ESI-MS m/z:499.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d6) δ: 10.38 (s, 1H), 8.17 (s, 1H),7.43-7.37 (m, 1H), 6.89-6.79 (m, 3H), 6.21-6.17 (dd, J=2.4, 16.8 Hz,1H), 5.76-5.74 (dd, J=2.1, 10.0 Hz, 1H), 4.10 (m, 4H), 3.88-3.79 (m,8H).

Example 151-(4-(6-chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 15 provides an exemplary procedure according to Method Q.

tert-Butyl4-(6-chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl4-(2,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(200 mg, 0.38 mmol), Pd₂(dba)₃ (35 mg, 0.038 mmol), Cs₂CO₃ (372 mg, 1.14mmol), Xantphos (22 mg, 0.038 mmol) and dimethylphosphine oxide (118 mg,1.52 mmol) in dioxane (25 mL) was stirred at reflux under N₂ for 5 h.The mixture was allowed to cool to RT, and partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (1-2% methanol/dichloromethane) toafford the desired product (129 mg, 60% yield) as a solid.

(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)dimethylphosphineOxide

A mixture oftert-butyl4-(6-chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(129 mg, 0.23 mmol) in dichloromethane (20 mL), TFA (5 mL) was added andthe resulting mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo to afford the crude product (106 mg) which wasused directly in the next step without further purification.

1-(4-(6-Chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)dimethylphosphineoxide (106 mg, 0.23 mmol) was added to the mixture of Et₃N (70 mg, 0.69mmol) in dichloromethane (10 mL). The mixture was stirred for 5 min andthen acryloyl chloride (25 mg, 0.27 mmol) was added. The resultingmixture was stirred at RT for 0.5 h, poured into water and thenextracted with dichloromethane. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (1-2%methanol/dichloromethane) to afford the desired product (60 mg, 51%yield) as a solid.

1-(4-(6-Chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-Chloro-2-(dimethylphosphoryl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(60 mg, 0.12 mmol) in dichloromethane (30 mL) at −78° C., BBr₃ (0.5 mL,5.3 mmol) was added. The reaction mixture was stirred at RT for 1 h.This mixture was quenched with saturated NaHCO₃ and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃aqueous solution and brine, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(5-10% methanol/dichloromethane) to afford the desired product (30 mg,52% yield) as a solid. ESI-MS m/z: 507.2 [M+H]⁺; ¹H-NMR (400 MHz,DMSO-d6) δ:10.35 (d, J=2.0 Hz, 1H), 8.09 (d, J=0.8 Hz, 1H), 7.41-7.35(m, 1H), 6.88-6.80 (m, 3H), 6.18 (dd, J=2.4, 16.8 Hz, 1H), 5.75 (dd,J=2.4, 10.0 Hz, 1H), 4.03-4.01 (m, 4H), 3.85-3.77 (m, 4H), 1.78 (s, 3H),1.75 (s, 3H).

Example 161-(4-(6-chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 16 provides and exemplary procedure according to Method R.

Methyl3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylate

To a mixture of3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicacid (2.0 g, 6.4 mmol) in DMF (15 mL) at RT, K₂CO₃ (1.8 g, 12.8 mmol)and CH₃I (1.1 g, 7.7 mmol) were added and the resulting mixture wasstirred at RT for 1 h. The mixture was poured into water, extracted withethyl acetate and washed with brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford thedesired product (2.0 g, 95% yield) as a solid.

6-Chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol

To a mixture of methyl3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylate(2.0 g, 6.12 mmol), 2-chloroacetonitrile (2.3 g, 30.6 mmol) in dioxane(30 mL), HCl (gas) was bubbled for 1 h and the resulting mixture wasstirred at 100° C. for 15 h. The mixture was allowed to cool to RT, andpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(10-20% ethyl acetate/petroleum ether) to afford the desired product(2.1 g, 93% yield) as a solid.

4,6-Dichloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

A mixture of6-chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol(2.1 g, 5.66 mmol), Et₃N (4 mL) in POCl₃ (40 mL) was stirred at 100° C.for 15 h. The mixture was concentrated in vacuo and partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo to afford the crude product (2.0g) which was used directly in the next step without furtherpurification.

tert-Butyl4-(6-chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a mixture of4,6-dichloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline(2.6 g, 5.13 mmol), Et₃N (1.6 g, 15.39 mmol) in THF (40 mL), tert-butylpiperazine-1-carboxylate (1.43 g, 7.69 mmol) was added. The resultingmixture was stirred at room temperature for 1 h, poured into water andthen extracted with MeOH/DCM. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (20-50% ethylacetate/petroleum ether) to afford the desired product (2.0 g, 72%yield) as a solid.

tert-Butyl4-(6-chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl4-(6-chloro-2-(chloromethyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(1.0 g, 1.86 mmol), KOH (312 mg, 1.14 mmol), and dimethylphosphine oxide(435 mg, 1.52 mmol) in DMSO (30 mL) was stirred at 100° C. for 15 h. Themixture was allowed to cool to RT, and then partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (1-5% methanol/dichloromethane) toafford the desired product (400 mg, 36% yield) as a solid.

((6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)methyl)dimethylphosphineOxide

To a mixture oftert-butyl4-(6-chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(400 mg, 0.69 mmol) in DCM (20 mL), TFA (5 mL) was added and theresulting mixture was stirred at RT for 1 h. The mixture wasconcentrated in vacuo to afford the crude product (200 mg) which wasused directly in the next step without further purification.

1-(4-(6-Chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

((6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazolin-2-yl)methyl)dimethylphosphineoxide (200 mg, 0.42 mmol) was added to the mixture of Et₃N (127 mg, 1.26mmol) in DCM (15 mL). The mixture was stirred for 5 min and thenacryloyl chloride (76 mg, 0.84 mmol) was added. The resulting mixturewas stirred at RT for 0.5 h, poured into water and then extracted withMeOH/DCM. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (1-2% methanol/dichloroethane) to affordthe desired product (150 mg, 68% yield) as a solid.

1-(4-(6-Chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-2-((dimethylphosphoryl)methyl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(150 mg, 0.28 mmol) in DCM (20 mL) at −78° C., BBr₃ (0.5 mL, 5.3 mmol)was added and the resulting mixture was stirred at RT for 1 h. Themixture was poured into ice water, NaHCO₃ (50 mL) was added and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (5-10%methanol/dichloroethane) to afford the desired product (90 mg, 62%yield) as a solid. ESI-MS m/z: 521.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6)δ: 10.31 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.40-7.34 (m, 1H), 6.88-6.80(m, 3H), 6.18 (dd, J=2.4, 16.8 Hz, 1H), 5.75 (dd, J=2.4, 10.0 Hz, 1H),3.92-3.77 (m, 8H), 3.45 (d, J=15.6 Hz, 2H), 1.57 (s, 3H), 1.54 (s, 3H).

Example 174-(4-acryloylpiperazin-1-yl)-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carbonitrile

Example 17 provides an exemplary method according to Method U.

7-Bromo-6-chloro-8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione

2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (5 g, 18.6 mmol) wasdissolved in THF (60 mL) in a 250 mL single neck flask, then cooled to0° C., bis(trichloromethyl) carbonate (5.52 g, 18.6 mmol) was addeddropwise. The mixture was warmed to 50° C. and stirred at 50° C. for 16h. The solvent was removed in vacuo. The residue was dissolved withethyl acetate. The mixture was washed with brine and saturated NaHCO₃solution. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=1:1) to givethe desired compound as yellow solid (2.3 g, 42% yield).

7-Bromo-6-chloro-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile

A mixture of 7-bromo-6-chloro-8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione(1.4 g, 4.75 mmol), ethyl 2-cyanoacetate (806 mg, 7.13 mmol) and Et₃N(1.92 g, 19.01 mmol) in DMF (30 mL) was stirred at 120° C. under argonfor 16 h. The mixture was allowed to cool to RT, and then washed with 1MHCl. The solid was collected by filtration, dried and give the targetcompound as brown solid (2.1 g, crude) without further purification usedin next step.

7-Bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile

7-Bromo-6-chloro-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile (1.8 g,5.67 mmol) in MeCN (5 mL) and POCl₃ (30 mL) was stirred at 90° C. for 16h. The mixture was evaporated under reduced pressure. The residue waspoured into dichloromethane/Et₃N (200/10 mL) solution and washed withice water. The mixture was extracted with ethyl acetate. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo to give thedesired product as brown solid (947 mg, crude) without furtherpurification used in next step.

tert-Butyl4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carbonitrile(200 mg, 0.56 mmol), tert-butyl piperazine-1-carboxylate (210 mg, 1.13mmol) and Et₃N (228 mg, 2.25 mmol) in dichloromethane (30 mL) wasstirred at RT for 1 h. The mixture was quenched with saturated NaHCO₃solution and partitioned between water and ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (ethyl acetate/petroleum ether=1:4) to afford the desired product(268 mg, 95% yield) as a yellow solid. ESI-MS m/z: 505.2 [M+H]⁺.

tert-Butyl4-(7-bromo-6-chloro-3-cyano-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate(268 mg, 0.53 mmol), N,N-dimethylazetidin-3-amine dihydrochloride (368mg, 2.12 mmol) and DIEA (549 mg, 4.25 mmol) in i-PrOH (20 mL) wasstirred at 120° C. for 1 h and then was allowed to cool to RT. Themixture was quenched with saturated NaHCO₃ solution and partitionedbetween water and ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel(MeOH/dichloromethane=1:40) to afford the desired product (189 mg, 62%yield) as a yellow solid. ESI-MS m/z: 569.3 [M+H]⁺.

tert-Butyl4-(3-cyano-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-6-methylquinolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-3-cyano-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinolin-4-yl)piperazine-1-carboxylate(189 mg, 0.33 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (208 mg,1.33 mmol), 1.5 M Na₂CO₃ solution (0.56 mL, 0.84 mmol) and Pd(PPh₃)₄(38mg, 0.033 mmol) in dioxane (30 mL) and H₂O (2 mL) was stirred at 80° C.under argon for 16 h. The mixture was evaporated. The residue waspurified by flash column chromatography on silica gel(MeOH/dichloromethane=1:40) to afford the desired product (85 mg, 19%yield) as a yellow solid. ESI-MS m/z: 599.35[M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-6-methylquinoline-3-carbonitrile

To a mixture of tert-butyl4-(6-chloro-3-cyano-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinolin-4-yl)piperazine-1-carboxylate(85 mg, 0.14 mmol) in dichloromethane (8 mL), TFA (2 mL) was added. Themixture was stirred at RT for 2 h and then concentrated in vacuo. Theresidue was dissolved in dichloromethane (20 ml), triethylamine (86 mg,0.85 mmol) and acryloyl chloride (26 mg, 0.28 mmol) were added at 0° C.The resulting mixture was stirred at RT for 10 min, and then quenchedwith sat. NaHCO₃ solution. The mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was dissolved in THF (20 mL) andwater (10 mL), LiOH.H₂O (30 mg, 0.71 mmol) was added. The mixture wasstirred at RT for 1.5 h, adjusted pH=8 with 1M HCl, and extracted withethyl acetate. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (MeOH/dichloromethane=1:40) and followed byPre-TLC to afford the desired product (35 mg, 45% yield) as a yellowsolid. ESI-MS m/z: 553.3[M+H]⁺; ¹H-NMR (400 MHz, DMSO-d6) δ: 10.25 (s,1H), 7.82 (s, 1H), 7.37-7.31 (m, 1H), 6.93-6.7 (m, 3H), 6.19 (dd, J=2.4,16.6 Hz, 1H), 5.75 (dd, J=2.3, 10.3 Hz, 1H), 4.31 (t, J=8.2 Hz, 2H),4.07-4.04 (m, 2H), 3.86-3.83 (m, 4H), 3.62 (brs, 4H), 3.19-3.17 (m, 1H),2.12 (s, 6H).

Example 181-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((3-fluoropyridin-2-yl)methoxy)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 18 provides an exemplary preparation according to GeneralSynthetic Method Q.

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-(((3-fluoropyridin-2-yl)methoxy)methyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(494 mg, 1 mmol), (3-fluoropyridin-2-yl)methanol (381 mg, 3 mmol) andBu₄NBr (322 mg, 1 mmol) in 5 mL of DCM, 5 mL of 20% NaOH aqueoussolution was added. The resulting mixture was stirred at 50° C. in asealed vial for 48 h. The mixture was allowed to cool to RT andpartitioned between DCM and water. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified viaIsolera One (MeOH/DCM=0-10%) to afford the desired product (450 mg. 77%yield).

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((3-fluoropyridin-2-yl)methoxy)methyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-(((3-fluoropyridin-2-yl)methoxy)methyl)quinazolin-4-yl)piperazine-1-carboxylatein two steps in analogous fashion to the sytnthesis of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-((1-methylpiperidin-4-yl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-onein Example 3. ¹H NMR (500 MHz, DMSO-d6) δ: 10.28 (s, 1H), 8.38 (d, J=6.0Hz, 1H), 8.02 (s, 1H), 7.71 (m, 1H), 7.45 (m, 1H), 7.36 (m, 1H),6.77-6.88 (m, 3H), 6.16 (d, J=2.5, 14.5 Hz, 1H), 5.73 (d, J=2.0, 8.5 Hz,1H), 4.85 (s, 2H), 4.68 (s, 2H), 3.70-3.98 (m, 8H); ESI-MS m/z: 569.6[M+H]⁺.

Example 191-(4-(6-chloro-7-(2,3-difluoro-6-hydroxyphenyl)-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 19 provides an exemplary preparation according to GeneralSynthetic Method R.

7-Bromo-6-chloro-8-fluoroquinazolin-4(3H)-one

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (21.2 g,79.1 mmol) in EtOH (200 mL) at room temperature, formarmidine acetate(82 g, 791 mmol) was added and the resulting mixture was stirred atreflux for 16 h. The mixture was concentrated in vacuo. The residue wasrinsed with H₂O and dried to afford the desired product as a gray solid(17.6 g, 80% yield). ESI-MS m/z: 278.9 [M+H]⁺.

7-Bromo-4,6-dichloro-8-fluoroquinazoline

A mixture of 7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one (17.6 g,63.43 mmol), SOCl₂ (300 mL) and DMF (12 drops) was stirred at reflux for16 h. The mixture was allowed to cool to room temperature and thenconcentrated in vacuo to afford the crude product (19.6 g). The crudeproduct was used in the next step without further purification.

tert-Butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 7-bromo-4,6-dichloro-8-fluoroquinazoline (19.6 g, 65.6mmol) in dichloromethane (150 mL) at room temperature, tert-butylpiperazine-1-carboxylate (24.6 g, 197 mmol) and Et₃N (27.5 mL, 197 mmol)were added. The resulting mixture was stirred at room temperature for 40min. The mixture was extracted with dichloromethane. The organic layerwas washed with 1N HCl, water, saturated NaHCO₃ solution and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was triturated with mixture of petroleum ether/ethyl acetate=5:1to afford the desired product as a white solid (26 g, 89% yield). ¹HNMR(400 MHz, CDCl₃) δ: 8.78 (S, 1H), 7.81 (d, J=2 Hz, 1H), 3.83-3.80 (m,4H), 3.68-3.66 (m, 4H), 1.52 (s, 9H); ESI-MS m/z: 446.1 [M+H]⁺.

tert-Butyl4-(6-chloro-7-(2,3-difluoro-6-hydroxyphenyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(405 mg, 1.0 eq.) in dioxane (10 mL) in the sealed tube,(2,3-difluoro-6-hydroxyphenyl)boronic acid (317 mg, 2.0 eq.), tetrakis(211 mg, 0.2 eq.) and aqueous Na₂CO₃ (1M, 3 mL) were added and theresulting mixture was stirred at 120° C. in the Microwave Reactor for 1h. After cooling down, it was filtered and partitioned between EtOAc andwater. The organic layer was dried with Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (DCM/MeOH=10:1) to afford the desiredproduct (87 mg, 19% yield) as a solid. ESI-MS m/z: 495.1 [M+H]⁺.

1-(4-(6-Chloro-7-(2,3-difluoro-6-hydroxyphenyl)-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of tert-butyl4-(6-chloro-7-(2,3-difluoro-6-hydroxyphenyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(87 mg, 1.0 eq.) in DCM (10 mL), TFA (1.3 mL) was added and theresulting mixture was stirred at RT for 1.5 h. The mixture wasconcentrated in vacuo. The residue was taken in ethyl acetate,neutralized with sat. NaHCO₃ aqueous solution, washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The crude product was used in thenext step directly.

At −78° C., DIEA (86 ul, 3.4 eq.) was added into the mixture of acrylicacid (12 μL, 1.12 eq.) and HATU (67 mg, 1.12 eq.) in DCM/DMF (2 mL/2 mL)and the resulting mixture was stirred for 10 min. Then cooling bath wasremoved and stirring was continued for 20 min at RT. At −78° C., it wasadded into the above obtained residue in DCM (10 mL). The reactionmixture was gradually warmed to RT and stirred for 2 h. The mixture wasdiluted with 20% isopropanol in DCM, washed with water and brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column purification (DCM/MeOH=10:1) to afford the desiredproduct (23 mg, 29% yield over two steps). ¹H NMR (500 MHz, DMSO-d6) δ:10.29 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.44 (dd, J=20, 9.5 Hz, 1H),6.82 (m, 2H), 6.17 (dd, J=16.5, 2 Hz, 1H), 5.74 (dd, J=10, 2.0 Hz, 1H),3.93-3.76 (m, 8H); ESI-MS m/z: 449.1 [M+H]⁺.

Example 201-(2-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one

Example 20 provides and exemplary procedure according to Method S.

6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol

To a solution of3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicacid (8.1 g, 25.88 mmol) in EtOH (100 mL, >99.7%) at RT, formimidamideacetate (35 g, 336.4 mmol) was added and the resulting mixture wasstirred at reflux for 16 h. The reaction mixture was concentrated invacuo to remove EtOH, and slowly added to H₂O, the mixture was filteredand the cake was dried to afford the desired product (7.5 g, 90.4%) as awhite solid.

4,6-Dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

A mixture of6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol (10 g,31.1 mmol), POCl₃ (100 mL) and DIPEA (10 mL) was stirred at reflux for16 h. The mixture was allowed to cool to RT and concentrated in vacuo toremove POCl₃. The residue was dissolved with ethyl acetate. The organiclayer was wash with brine, dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash chromatography on silica gel(ethyl acetate/petroleum ether=2.5-10%) to afford the product (9.3 g,87.7% yield) as a brown solid.

tert-Butyl2-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate

A mixture of4,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline (100 mg,0.29 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (80 mg,0.37 mmol), TEA (60 mg, 0.58 mmol) and dichloromethane (5 mL) wasstirred at RT for 0.5 h. The mixture was quenched with saturated NaHCO₃solution and partitioned between water and ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (ethyl acetate/petroleum ether=1:5) to afford the desired product(120 mg, 80% yield) as white solid.

2-(6-Chloro-8-fluoro-4-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-7-yl)-3-fluorophenol

A mixture of2-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate(120 mg, 0.23 mmol), TFA (2 mL) and DCM (5 mL) was stirred at RT for 1h. The mixture was concentrated in vacuo. The residue was dissolved inDCM (5 mL) and cooled to −78° C., BBr₃ (1 mL, 10.79 mmol) was added tothe mixture at −78° C. The reaction mixture was stirred at RT for 1 h.This mixture was quenched with saturated NaHCO₃ and extracted withdichloromethane. The organic layer was washed with saturated NaHCO₃aqueous solution and brine, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(5-10% methanol/dichloroethane) to afford the desired product (20 mg,21% yield) as a solid.

1-(2-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one

To a mixture of2-(6-chloro-8-fluoro-4-(2,6-diazaspiro[3.4]octan-2-yl)quinazolin-7-yl)-3-fluoropheno(20 mg, 0.05 mmol) and TEA (20 mg, 0.2 mmol) in dichloromethane (3 mL)at RT, acryloyl chloride (6 mg, 1.2 mmol) was added and the resultingmixture was stirred at RT for 1 h. The mixture was quenched withsaturated NaHCO₃ solution. The mixture was extracted with ethyl acetate.The organic layer was dried over Na₂SO₄, and concentrated in vacuo. Theresidue was dissolved in THF/H₂O (3 mL/1.5 mL), LiOH.H₂O (21 mg, 0.5mmol) was added. The mixture was stirred at RT for 1 h and then 1M HClsolution was added to adjust the pH to 6. The mixture was extracted withethyl acetate. The organic layer was dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by silica chromatography on silicagel (DCM:MeOH=50:1 to 20:1) to give the crude compound, which wasfurther purified by Pre-TLC to give the target compound (4 mg, 18%yield) as white solid. ESI-MS m/z: 457.1 [M+H]⁺; ¹H-NMR (400 MHz, CDCl₃)δ: 8.40-8.38 (m, 1H), 7.57 (s, 1H), 7.37-7.31 (m, 1H), 6.92-6.90 (m,1H), 6.79-6.74 (m, 1H), 6.46-6.38 (m, 2H), 5.79-5.72 (m, 1H), 4.50-4.43(m, 4H), 3.88-3.78 (m, 2H), 3.75-3.62 (m, 2H), 2.35-2.31 (m, 1H),2.29-2.22 (m, 1H).

Example 21N-(3-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)phenyl)acrylamide

Example 21 provides an exemplary procedure according to Method T.

6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(3-nitrophenyl)quinazoline

To a stirred solution of4,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline (380 mg,1.12 mmol) in THF (30 mL), 3-nitrophenylboronic acid (560 mg, 3.36mmol), PdCl₂(PPh₃)₂(84 mg, 0.12 mmol) and K₃PO₄ (1.2 g, 5.6 mmol) wereadded and the resulting mixture was stirred at 80° C. under nitrogenovernight. The mixture was allowed to cool to RT and partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to afford the desired product (180 mg,42.2% yield) as an off white solid.

3-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)benzenamine

To a solution of6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(3-nitrophenyl)quinazoline(360 mg, 0.42 mmol) in CH₃CH₂OH (30 mL) was added SnCl₂ (396 mg, 2.10mmol) and the resulting mixture was stirred at 70° C. for 5 h. Themixture cooled to RT and partitioned between saturated NaHCO₃ solution(40 mL) and ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (petroleum ether/ethylacetate=10:1) to afford the desire product (140 mg, 83.3% yield) as anoff-white solid.

2-(4-(3-Aminophenyl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenol

To a solution of3-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)benzenamine(140 mg, 0.35 mmol) in dichloromethane (20 mL) at −78° C., BBr₃ (880 mg,3.5 mmol) was added drop wise and the resulting mixture was stirred atRT for 8 h. The mixture was cooled to −10° C., NaHCO₃ solution was addedto adjust pH>7, and then extracted with dichloromethane. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum ether/ethyl acetate=1:1) followed by Pre-HPLC to affordthe desire product (60 mg, 44.6% yield) as an off-white solid.

2-(4-(3-(Acrylamido)phenyl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenylAcrylate

To a solution of2-(4-(3-aminophenyl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenol(60 mg, 0.156 mmol) in dichloromethane (20 mL) at 0° C., acryloylchloride (72 mg, 0.78 mmol) and Et₃N (158 mg, 1.56 mmol) were added andthe resulting mixture was allowed to warm to RT and stirred at RT for 3h. The mixture was quenched with H₂O and extracted with dichloromethane.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford a crude desired product (75 mg, 91.7%yield) as an off-white solid.

N-(3-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)phenyl)acrylamide

To a solution of2-(4-(3-(acrylamido)phenyl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenylacrylate (75 mg, 0.143 mmol) in THF (10 mL) and H₂O (10 mL), LiOH.H₂O(18 mg, 0.428 mmol) was added and the resulting mixture was stirred atRT for 2 h. The mixture was partitioned between water and ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (petroleum ether/ethyl acetate=1:1) toafford the desired product (30 mg, 48% yield) as an off-white solid.ESI-MS m/z: 438.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ: 10.47-10.42 (m,1H), 9.49 (s, 1H), 8.21 (s, 1H), 8.14-8.13 (m, 1H), 7.96-7.94 (m, 1H),7.66-7.58 (m, 2H), 7.45-7.39 (m, 1H), 6.91-6.84 (m, 2H), 6.51-6.45 (m,1H), 6.34-6.29 (dd, J=2.0, 16.8 Hz, 1H), 5.83-5.80 (dd, J=2.0, 10.4 Hz,1H).

Example 222-(4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenylDihydrogen Phosphate

To a stirred solution of(S)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(400 mg, 0.93 mmol) in anhydrous DCM (5 mL) at 0° C. under nitrogen(prepared according to the above general procedures), pyridine (1.54 g,19.5 mmol) was added followed by slow addition of POCl₃ solution (1.42g, 9.3 mmol) in 5 mL of dry DCM (over 10 min). After addition of POCl₃,the reaction mixture was stirred at 0° C. for 2 h. The reaction was thenquenched by dropwise addition of 1:1 mixture of acetone/water (6 mL) andthe resulting mixture was stirred at RT overnight. The mixture wasconcentrated in vacuo, and the residue purified by pre-HPLC to affordthe desired product (274 mg, 58% yield). ESI-MS m/z: 511.0 [M+H]⁺;¹H-NMR (500 MHz, DMSO-d6) δ: 8.91 (s, 1H), 8.13 (s, 1H), 7.57 (dd,J=8.5, 15.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.20 (t, J=8.5, 8.5 Hz,1H), 6.83 (dd, J=10.5, 17.0 Hz, 1H), 6.17 (dd, J=2.5, 17.0 Hz, 1H), 5.74(dd, J=2.5, 11.5 Hz, 1H), 3.75-3.95 (m, 8H).

Example 23(S)-(2-(4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenoxy)methylDihydrogen Phosphate

(S)-(2-(4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenoxy)methyldi-tert-butyl Phosphate

(S)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(722 mg, 1.68 mmol), sodium hydride (60%, 370 mg, 9.2 mmol),tetrabutylammonium iodide (208 mg, 0.56 mmol,) were charged to a flaskand cooled down to −78° C. Di-tert-butyl (chloromethyl) phosphate (2.7g, 10.4 mmol) was dissolved in cold DMF (4 mL) and was added inportions. THF (2 mL) was added to solubilize the mixture at −78° C. TheReaction was vigorously stirred and slowly warmed up to 0° C. in 4 h,and the resulting mixture was stirred at RT for another 4 hours.Reaction was diluted with DCM (100 mL), filtered, cooled down to −78°C., and treated with ice. Reaction was then warmed up to RT, washed withbrine and water, dried over Na₂SO₄, and concentrated in vacuo. Theresidue obtained was purified on silica gel (0-6% methanol in DCM) toafford the desired product. The product was directly used in the nextstep. ESI-MS m/z: 653.2 [M+H]⁺.

(S)-(2-(4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenoxy)methylDihydrogen Phosphate

(S)-(2-(4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenoxy)methyldi-tert-butyl phosphate (about 1.1 g, 1.68 mmol,) was dissolved in 1:1mixture of DCMITFA (2 mL). The mixture was vigorously stirred at RT for20 min, stripped off solvents, and then purified by prep-HPLC (5-60%MeCN in water) to give the desired product (138 mg, 15% yield). ESI-MSm/z: 541.0 [M+H]⁺; ¹H-NMR (500 MHz, DMSO-d6) δ: 8.69 (s, 1H), 8.05 (s,1H), 7.60 (q, J1=6.4 Hz, J2=12.0 Hz, 1H), 7.26 (d, J=6.8 Hz, 1H), 7.13(t, J=6.8 Hz, 1H), 6.82 (dd, J1=8.4 Hz, J2=13.6 Hz), 6.17 (dd, J1=2 Hz,J2=13.6 Hz, 1H), 5.74 (dd, J1=2 Hz, J2=8.4 Hz), 5.48 (m, 2H), 3.90-6.70(br m, 12).

Example 24 Synthesis of 1-((3S)-4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Example 24 provides an exemplary preparation according to GeneralSynthetic Method V.

tert-Butyl(S)-4-(6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate

To a mixture of 800 mg (4.04 mmol, 1.0 eq.) of6-chloro-8-fluoroquinazolin-4(3H)-one and BOP (1.1 eq.) in acetonitrile,DBU (1.3 eq.) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (1.1eq.) were added sequentially. The resulting mixture was stirred at80-100° C. for 37 h. The mixture was cooled down, concentrated in vacuoand then partitioned between water and ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash column chromatography (stepwise gradient of 0-10% MeOH indichloromethane) to afford the desired product (685 mg, 45% yield).

tert-Butyl(3S)-4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate

A flame dried round bottle (evacuated under vacuum and filled with N₂)was fitted with mechanical stirring, and charged with tert-butyl(S)-4-(6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate(685 mg, 1.80 mmol, 1.0 eq.) solution in dry THF.Bis(2,2,6,6-tetramethylpiperidinyl)zinc, lithium chloride, magnesiumchloride complex ((TMP)₂Zn.2 MgCl₂.2 LiCl) (0.35 M solution inTHF/toluene, 1.0 eq.) was dropwise added. The reaction was allowed tostir for 45 min at RT and then degassed by bubbling nitrogen through thesolution for 15 min. Solid 2-bromo-1-fluoro-3-methoxybenzene (1.0 eq.)and CPhos 3rd generation precatalyst (0.1 eq.) were added, and theresulting mixture was stirred at 40° C. for 16 h. The reaction mixturewas concentrated in vacuo, dissolved in ethyl acetate, cooled in an icebath, and quenched with a 1:1 solution of saturated ammonium chlorideand H₂O. The layers were separated, and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (stepwise gradient of 20%-30% EtOAc in hexanes) toafford the desired product (504 mg, 56% yield).

1-((3S)-4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

At −78° C., BBr₃ in dichloromethane (1M, 6.0 eq.) was dropwise addedinto tert-butyl (3S)-4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate(228 mg, 0.45 mmol, 1.0 eq.) solution in dichloromethane. After additionwas complete, the reaction was warmed to RT, and the suspension wasstirred for 19 h. The reaction was cooled to 0° C. and quenched with anice/water. Additional water was added and the layers were separated. Thewater layer was collected. The organic layer was extracted with water.The combined water layer was concentrated, added 2-MeTHF and solidNaHCO₃ (20.0 eq.). The reaction mixture was allowed to stir for 5 min.The acryloyl chloride (2.5 eq.) was added at RT and the resultingmixture was stirred at RT for 1 h. Then 5 N NaOH (0.5 mL) was added toquench the reaction, followed by adding lmL of 1 N HCl forneutralization. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate. The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash column chromatography (stepwise gradientof 0-10% MeOH in dichloromethane) to afford the desired product (104 mg,52% yield). ESI-MS m/z: 445.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d6) δ 10.27(s, 1H), 8.70 (s, 1H), 7.94 (s, 1H), 7.39-7.34 (q, J=8.5 Hz, 1H),6.87-6.80 (m, 3H), 6.21-6.16 (m, 1H), 5.43 (dd, J=10, 2.5 Hz, 1H), 4.78(broad s, 1H), 4.40-3.96 (m, 4H), 3.70-3.61 (m, 2H), 1.30 (s, 3H).

Example 25 Synthesis of 4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carbonitrile

Example 25 provides an exemplary preparation according to GeneralSynthetic Method W.

3-Bromo-4-chloro-2-fluorobenzenamine

To a solution of 3-bromo-2-fluorobenzenamine (1.9 g, 10 mmol) in DMF (10mL) at RT, NCS (1.4 g, 10.5 mmol) was added and the resulting mixturewas stirred at RT for 16 h. The mixture was poured into ice water andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (petroleum ether/ethyl acetate=30:1)to afford the desired product (1.15 g, 51% yield). ESI-MSm/z: 225.9[M+H]⁺.

Diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino)methylene)malonate

A mixture of 3-bromo-4-chloro-2-fluorobenzenamine (2.3 g, 10.2 mmol) anddiethyl2-(ethoxymethylene) malonate (2.42 g, 11.22 mmol) was stirred at120° C. for 3 h. The mixture was allowed to cool to RT, petroleum wasadded and the resulting mixture was stirred at RT for 1 h. Theprecipitate was collected by filtration and dried to afford the desiredproduct (2.76 g, 68.7% yield). ESI-MS m/z: 395.9[M+H]⁺.

Ethyl 7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

Diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino)methylene)malonate(2.76 g, 6.99 mmol) was suspended in Ph₂O (20 mL). The mixture wasstirred at 250° C. for 2 h. The mixture was allowed to cool to RT andthen 100 mL of petroleum ether was added. The white solid was collectedby filtration and rinsed with petroleum ether (100 mL) to afford thedesired product (1.85 g, 76% yield). ESI-MS m/z: 349.9 [M+H]⁺.

Ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3-carboxylate

A mixture of ethyl7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate (1.85 g, 5.31mmol) and POCl₃ (10 mL) was stirred at reflux for 4 h. The mixture wasallowed to cool to RT and concentrated in vacuo to afford the crudeproduct (1.41 g).

Ethyl7-bromo-4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoroquinoline-3-carboxylate

A mixture of ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3-carboxylate(552 mg, 1.50 mmol), (2R,6S)-tert-butyl2,6-dimethylpiperazine-1-carboxylate (644 mg, 3.0 mmol), DIPEA (774 mg,6.0 mmol) in dioxane (40 mL) was stirred at 90° C. under argon for 2 h.The mixture was cooled to RT and then concentrated in vacuo. The residuewas purified by column chromatography on silica gel (petroleumether/ethyl acetate=3:1) to afford the desired product as a yellow solid(794 mg, 94.7% yield). ESI-MS m/z: 546.3 [M+H]⁺.

Ethyl4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxylate

A mixture of ethyl 7-bromo-4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoroquinoline-3-carboxylate(794 mg, 1.46 mmol) and (2-fluoro-6-methoxyphenyl)boronic acid (1.24 g,7.29 mmol) and Na₂CO₃ (464 mg, 4.37 mmol) in H₂O (20 mL) and dioxane (80mL) under argon, Pd(PPh₃)₄(201 mg, 0.17 mmol) was added and theresulting mixture was stirred at 90° C. for 16 h. The mixture wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate=4:1) toafford the desired product (178 mg, 20.7% yield).

4-((3R,5S)-4-(tert-Butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxylicacid

A mixture of ethyl 4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxylate(178 mg, 0.30 mmol) in THF (10 mL) and water (10 mL), lithium hydroxide(51 mg, 1.21 mmol) was added and the resulting mixture was stirred at RTfor 16 h. The mixture was diluted with 2M NaOH (30 mL), and extractedwith 50% ethyl acetate/petroleum ether. The water phase was acidified by1M HCl and extracted with ethyl acetate. The organic layer wasconcentrated in vacuo to afford the crude product (189 mg) which wasused in the next step directly.

(2R,6S)-tert-Butyl4-(3-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of 4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxylicacid (189 mg, 0.34 mmol) and NH₄Cl (54 mg, 1.01 mmol) and Py-BOP (350mg, 0.67 mmol) in DMF (20 mL), DIPEA (174 mg, 1.34 mmol) was added andthe resulting mixture was stirred at RT for 30 min. The mixture waspartitioned between water and ethyl acetate. The organic layer wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (dichloromethane/MeOH=30:1) to afford acrude product (310 mg). ESI-MS m/z: 561.4 [M+H]⁺.

4-((3R,5S)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxamide

A mixture of (2R,6S)-tert-butyl4-(3-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate(310 mg) in dichloromethane (10 mL), TFA (3 mL) was added and theresulting mixture was stirred at RT for 30 min. The mixture was addeddrop wise to a stirred mixture of 2M NaOH (40 mL) and ethyl acetate (40mL). Then acryloyl chloride (1.5 mL) was added drop wise to thereaction. The mixture was extracted with ethyl acetate. The residue waspurified by column chromatography on silica gel (DCM/MeOH=30:1) toafford the desired product (84 mg). ESI-MS m/z: 515.30 [M+H]⁺.

4-((3R,5S)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carboxamide

A mixture of 4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxamide(84 mg, 0.16 mmol) in dichloromethane (10 mL) at −78° C., BBr₃ (409 mg,1.63 mmol) was added and the resulting mixture was stirred at RT for 2h. The mixture was poured to ice water, partitioned between ethylacetate and NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (57 mg). ESI-MS m/z:501.2 [M+H]⁺.

4-((3R,5S)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carbonitrile

To a solution of 4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carboxamide(57 mg) and Et₃N (10 mL), (CF₃CO)₂O (1.5 mL) was added. The mixture wasstirred at RT for 10 min, and quenched with water (50 mL). The mixturewas extracted by DCM (10 mL×2). The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (dichloromethane/MeOH=50:1) followedby Pre-TLC to afford the desire product (30 mg, 35% yield). ESI-MS m/z:483.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ: 10.45 (s, 1H), 8.96 (s, 1H),8.39 (s, 1H), 7.42 (t, J=8.4 Hz, J₂=15.6 Hz, 1H), 6.90 (m, 3H), 6.23(dd, J₁=1.6 Hz, J₂=16.4 Hz, 1H), 5.78 (dd, J₁=2.0 Hz, J₂=10.4 Hz, 1H),4.63 (m, 2H), 3.76 (m, 4H), 1.53 (m, 6H).

Example 26 Synthesis of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

Example 26 provides an exemplary preparation according to GeneralSynthetic Method U.

3-bromo-2-fluorobenzenamine

To a mixture of 1-bromo-2-fluoro-3-nitrobenzene (50 g, 228.4 mmol), HOAc(41.1 g, 685.2 mmol), EtOH (420 mL) and H₂O (140 mL) at roomtemperature, iron powder (38.4 g, 685.2 mmol) was added portion-wise.The resulting mixture was stirred at room temperature for 16 h and thenwas neutralized with NaOH (5 N) solution. Then the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (petroleum ether) to afford thecrude product (48 g, 111% yield) as a brown oil.

N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide

A mixture of 2,2,2-Trichloroethane-1,1-diol (37.7 g, 228.6 mmol) andNa₂SO₄ (243.5 g, 1714.5 mmol) were dissolved in water (600 mL) at 60° C.to be a clear solution. 3-bromo-2-fluorobenzenamine (36 g, 190.5 mmol)was added. Then the mixture was stirred at 60° C. for 1 h, followed by35% aqueous HCl (31.7 mL, 381 mmol). Then this mixture was stirred at60° C. for 1 h. Then hydroxylamine hydrochloride (65.7 g, 952.5 mmol)was added. The resulting mixture was stirred at 60° C. for 4 h and 100°C. for 16 h. Then the yellow precipitate was formed. The mixture wascooled to room temperature, the solid was filtered, washed with water,and dried in the air to afford the desired product (38.9 g, 78% yield).

6-bromo-7-fluoroindoline-2,3-dione

To the concentrated sulfuric acid (270 mL) at 60° C. was addedN-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide (29.4 g, 113.1mmol). The temperature was raised to 90° C. and maintained for 1 h. Thenthe TLC show complete consumption of the starting material. The reactionmixture was cooled to room temperature and poured into ice to get yellowprecipitate. Then the mixture was extracted with ethyl acetate. Theorganic layer was washed with water, Sa. NaHCO₃ and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/ethyl acetate=200:1 to20:1) to afford the crude desired product as a yellow solid (18.9 g, 68%yield). ESI-MS m/z: 278.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ: 11.75 (s,1H), 7.39 (dd, J=5.7, 7.9 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H).

2-amino-4-bromo-3-fluorobenzoic Acid

To a mixture of 6-bromo-7-fluoroindoline-2,3-dione (18.9 g, 77.5 mmol)in 2 N NaOH (350 mL) was added H₂O₂(30%, 40 mL) at 0° C. Then themixture was warmed to RT and stirred at RT for 16 h. The mixture wasquenched with Na₂SO₃, and solution was acidified with Conc. HCl toadjust pH=2. The precipitate was formed, filtered and dried in the airto afford the desired product as a white solid (17 g, 94% yield).

2-amino-4-bromo-5-chloro-3-fluorobenzoic Acid

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (17 g, 72.6 mmol)in DMF (200 mL) was added NCS (10.2 g, 76.2 mmol) at rt, the mixture wasstirred at 70° C. for 16 h. The mixture was cooled to rt and poured intocold brine, the precipitate was filtered, washed with water and dried toafford the desired product as a white solid (14.6 g, 75% yield). ESI-MSm/z: 269.8 [M+H]⁺.

7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (21.2 g,79.1 mmol) in EtOH (200 mL) was added formamidine acetate (82 g, 791mmol) at room temperature. The mixture was stirred at reflux for 16 h.Then mixture was evaporated, the solid was washed with H₂O, dried overair to afford the desired product as a gray solid (17.6 g, 80% yield).ESI-MS m/z: 278.9 [M+H]⁺.

7-Bromo-4,6-dichloro-8-fluoroquinazoline

A mixture of 7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one (2 g, 7.21mmol), SOCl₂ (30 mL) and DMF (2 drops) was stirred at reflux for 16 h.The mixture was cooled to RT and concentrated in vacuo to afford thecrude product (2.4 g) using in the next step without furtherpurification.

tert-Butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)-2-methylpiperazine-1-carboxylate

To a solution of 7-bromo-4,6-dichloro-8-fluoroquinazoline (2.4 g, 8.25mmol) in dichloromethane (25 mL) at RT, tert-butyl2-methylpiperazine-1-carboxylate (3.3 g, 16.5 mmol) and Et₃N (5.3 g,41.25 mmol) was added. The resulting mixture was stirred at RT for 40min. The mixture was extracted with dichloromethane. The organic layerwas washed with 1N HCl, water, saturated NaHCO₃ solution and brine. Theorganic dried over Na₂SO₄ and concentrated. The residue was washed withmixture of petroleum ether/ethyl acetate=5:1 to afford the desiredproduct as a white solid (2.8 g, 74% yield).

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2-methylpiperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)-2-methylpiperazine-1-carboxylate(1 g, 2.18 mmol), 2-fluoro-6-hydroxyphenylboronic acid (1.7 g, 10.9mmol), Pd(PPh₃)₄(252 mg, 0.218 mmol) and Na₂CO₃ (693 mg, 6.54 mmol) in1,4-dioxane/H₂O (40 mL/10 mL) was stirred at 90° C. for 16 h underargon. The mixture was allowed to cool to RT and concentrated in vacuo.The residue was purified by column chromatography on silica gel(dichloromethane/methanol=100:1) to afford the desired product (700 mg,65% yield). ESI-MS m/z: 491.2 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one

A mixture of tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2-methylpiperazine-1-carboxylate(150 mg, 0.30 mmol) and HCl in MeOH (10 mL, 4 N) was stirred at RT for 1h. The mixture was concentrated in vacuo to yield the crude productwhich was used directly in next step without further purification. Theabove obtained crude was dissolved in Et₃N (157 mg, 1.55 mmol) anddichloromethane (15 mL) and cooled to −20° C. To this mixture, acryloylchloride (69 mg, 0.76 mmol) was added. The resulting mixture was stirredat 0° C. for 2 h. The reaction mixture was quenched with saturatedNaHCO₃ solution, and then extracted with ethyl acetate. The organiclayer was washed with saturated NaHCO₃ solution and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was dissolved in THF/H₂O(10 mL/2 mL), LiOH.H₂O (52 mg, 1.24 mmol) was added and the resultingmixture was stirred for 1 h. The mixture was adjusted pH to 8 by 1N HClaqueous solution and NaHCO₃ aqueous solution and then extracted withethyl acetate. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (dichloromethane/methanol=20:1) to afford the product (32mg, 23% yield in 3 steps). ESI-MS m/z: 445.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d6) δ: 10.34 (s, 1H), 8.69 (s, 1H), 8.07 (s, 1H), 7.41-7.35 (m,1H), 6.89-6.77 (m, 3H), 6.17 (d, J=16.4 Hz, 1H), 5.73 (d, J=10.4 Hz,1H), 4.70-4.52 (m, 1H), 4.34-4.32 (m, 1H), 4.18-4.14 (m, 1H), 3.79-3.75(m, 1H), 3.53-3.52 (m, 2H), 3.68 (m, 1H), 1.13 (m, 3H).

Example 27 Synthesis of1-((2S,6R)-4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one

Example 27 provides an exemplary preparation according to GeneralSynthetic Method U.

a3-Amino-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylic Acid

To a stirred solution of 2-amino-4-bromo-3-fluorobenzoic acid (10 g, 43mmol) in 1,4-dioxane (400 mL) and H₂O (100 mL),2-fluoro-6-methoxyphenylboronic acid (36 g, 213 mmol),tetrakis(triphenylphosphine)palladium (2.5 g, 2.15 mmol) and Na₂CO₃ (27g, 258 mmol) were added. The mixture was degassed and back-filled withN₂ several times, and then heated to 100° C. and was stirred overnight.The mixture was allowed to cool to RT, water (500 mL) was added, andthen extracted with ethyl acetate (200 mL×2). The organic layer wasdiscarded, and 1M HCl solution was added to aqueous phase to adjustpH<3. The aqueous phase was extracted with ethyl acetate (200 mL×2),washed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe desired product (11 g, 92% yield) as a white solid. ESI-MS m/z:280.1 [M+H]⁺.

3-Amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylicAcid

To a solution of3-amino-2,2′-difluoro-6′-methoxy-[1,1′-biphenyl]-4-carboxylic acid (1μg, 39.6 mmol) in N,N-dimethylformamide (100 mL) at RT,N-chlorosuccinimde (5.27 g, 39.6 mmol) was added. The resulting mixturewas stirred at 100° C. for 1 h. The mixture was allowed to cool to RT,and the reaction mixture was slowly added to water (300 mL). The mixturewas filtered and the cake was dried to afford the desired product (11.5g, 93.1% yield) as a brown solid.

6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol

A mixture of3-amino-6-chloro-2,2′-difluoro-6′-methoxy-[1,1-biphenyl]-4-carboxylicacid (8.1 g, 25.8 mmol) in EtOH (>99%) (150 mL), formimidamide acetate(35 g, 336.4 mmol) was added. The mixture was stirred at 100° C.overnight. The reaction mixture was concentrated in vacuo and water wasadded. The mixture was filter and the cake was dried to afford thedesired product (7.5 g, 90.3%) as a light yellow solid.

4,6-Dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

The mixture of6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-ol (10 g,31.1 mmol) in POCl₃ (100 mL) and DIPEA (10 mL) were stirred at refluxfor 16 h. The mixture was allowed to cool to RT and concentrated invacuo to remove POCl₃. The residue was dissolved in ethyl acetate,washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography on silica gel(ethyl acetate/petroleum ether=2.5-10%) to afford the product (9.3 g,88% yield) as a brown solid.

(2S,6R)-tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of4,6-dichloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline (250 mg,0.733 mmol) in dioxane (30 mL) at RT, DIEA (303 mg, 2.35 mmol) and(2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (251 mg, 1.17mmol) were added. The resulting mixture was stirred at 90° C. for 30min. The mixture was concentrated in vacuo and the residue was purifiedby column chromatography on silica gel (ethyl acetate/petroleumether=1:3) to afford the desired product (346 mg, 91% yield). ESI-MSm/z: 519.3 [M+H]⁺

6-Chloro-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline

To a solution of (2S,6R)-tert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate(346 mg, 0.67 mmol) in DCM (8 mL), TFA (2 mL) was added and theresulting mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo. The residue was extracted with ethyl acetate andwashed with NaHCO₃ aqueous solution. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to afford the desired product(263 mg, 94% yield) as a solid. ESI-MS m/z: 419.1 [M+H]⁺.

2-(6-Chloro-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-8-fluoroquinazolin-7-yl)-3-fluorophenol

To a solution of 6-chloro-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazoline(263 mg, 0.63 mmol) in DCM (15 mL) at −78° C., BBr₃ (784 mg, 3.14 mmol)was added and the resulting mixture was stirred at RT for 2 h. Themixture was poured to ice water and extracted with ethyl acetate. Theorganic layer was washed with NaHCO₃ aqueous solution, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (dichloromethane/methanol=20:1) toafford the desired product (160 mg, 63% yield). ESI-MS m/z: 405.1[M+H]⁺.

2-(4-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenylAcrylate

To a solution of 2-(6-chloro-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-8-fluoroquinazolin-7-yl)-3-fluorophenol(80 mg, 0.19 mmol) and Et₃N (120 mg, 1.19 mmol) in DCM (20 mL) at 0° C.,acryloyl chloride (143 mg, 1.58 mmol) was added and the resultingmixture was stirred for 30 min. The mixture was extracted withdichloromethane and washed with NaHCO₃ aqueous solution. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toafford the crude product (130 mg).

1-((2S,6R)-4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)-2,6-dimethylpiperazin-1-yl)prop-2-en-1-one

To a solution of 2-(4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-8-fluoroquinazolin-7-yl)-3-fluorophenylacrylate (130 mg, crude) in THF (5 mL) and water (5 mL), lithiumhydroxide (83 mg, 1.98 mmol) was added and the resulting mixture wasstirred at RT for 1 h. The mixture was acidified with 1N HCl to adjustpH to 8, and then extracted with ethyl acetate. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel(dichloromethane/methanol=20:1) to afford the product (51 mg, 56% yieldin 2 steps). ESI-MS m/z: 459.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ:10.36 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.40 (t, J₁=7.2 Hz, J₂=14.4Hz, 1H), 6.89 (m, 3H), 6.21 (d, J=16.4 Hz, 1H), 5.75 (m, 1H), 4.59 (m,2H), 4.26 (m, 2H), 3.48 (m, 2H), 1.40 (m, 6H).

Example 28 Biochemical Assay of the Compounds

Test compounds were prepared as 10 mM stock solutions in DMSO (Fishercat# BP-231-100). KRAS G12C 1-169, his-tagged protein, GDP-loaded wasdiluted to 2 μm in buffer (20 mM Hepes, 150 mM NaCl, 1 mM MgCl₂).Compounds were tested for activity as follows:

Compounds were diluted to 50× final test concentration in DMSO in96-well storage plates. Compound stock solutions were vortexed beforeuse and observed carefully for any sign of precipitation. Dilutions wereas follow:

-   -   For 100 μM final compound concentration, compounds were diluted        to 5000 μM (5 μl 10 mM compound stock+5 μl DMSO and mixed well        by pipetting.    -   For 30 μM final compound concentration, compounds were diluted        to 1500 μM (3 μl 10 mM compound stock+17p DMSO) and mixed well        by pipetting.    -   For 10 μM final compound concentration, compounds were diluted        to 500 μM (2 μl 10 mM compound stock+38p DMSO) and mixed well by        pipetting. 49p of the stock protein solution was added to each        well of a 96-well PCR plate (Fisher cat#1423027). 1 μl of the        diluted 50× compounds were added to appropriate wells in the PCR        plate using 12-channel pipettor. Reactions were mixed carefully        and thoroughly by pipetting up/down with a 200·1 multi-channel        pipettor. The plate was sealed well with aluminum plate seal,        and stored in drawer at room temperature for 30 min, 2 hour or        24 hrs. 5·1 of 2% formic acid (Fisher cat# A117) in DI H₂O was        then added to each well followed by mixing with a pipette. The        plate was then resealed with aluminum seal and stored on dry ice        until analyzed as described below.

The above described assays were analyzed by mass spectrometry accordingto one of the following two procedures:

RapidFire/TOF Assay:

The MS instrument is set to positive polarity, 2 GHz resolution, and lowmass (1700) mode and allowed to equilibrate for 30 minutes. Theinstrument is then calibrated, switched to acquisition mode and theappropriate method loaded.

After another 30 minute equilibration time, a blank batch (i.e., buffer)is run to ensure equipment is operating properly. The samples are thawedat 37° C. for 10 minutes, briefly centrifuged, and transfer to the benchtop. Wells A1 and H12 are spiked with 1 uL 500 uM internal standardpeptide, and the plates centrifuged at 2000×g for 5 minutes. The methodis then run and masses of each individual well recorded.

The masses (for which integration data is desired) for each well arepasted into the platemap and exported from the analysis. Masses for theinternal standards are exported as well. The data at 50 ppm is extractedfor the +19 charge state, and identity of well A1 is assigned using theinternal standard spike and integrated. Peak data is exported as a TOFlist and the above steps are repeated individually, for the +20, 21, 22,23, 24, and 25 charge states.

Q-Exactive Assay:

The masses and peak intensities of KRAS G12C protein species weremeasured using a Dionex RSLCnano system (Thermo Scientific) connected toa Q Exactive Plus mass spectrometer (Thermo Scientific).

20 mL of sample was each loaded onto a Aeris™ 3.6 m WIDEPORE C4 200 Å,LC Column 50×2.1 mm column maintained at 40° C. at a flow rate of 600 μlmin⁻¹ with 20% Solvent A (0.1% formic acid in H₂O) and 80% Solvent B(0.1% formic acid in acetonitrile). The liquid chromatography conditionswere 20% solvent B for 1 min, 20% to 60% solvent B for 1.5 min, 60% to90% solvent for 0.5 min, 90% solvent B for 0.2 min, 90% to 20% solvent Bfor 0.2 min, and then equilibrated for 1.6 min before the followingsample injection. The flow rate was maintained at 600 μl min⁻¹throughout the sample analysis.

The mass spectrometer was operated in profile mode at a resolution of17500, 5 microscans, using 50 msec max injection time and an AGC targetof 1e6, and a full mass range from 800-1850 m/z was recorded. The HCDtrapping gas was optimized for maximum sensitivity for intact proteins.The ionization method was electrospray ionization, which used a sprayvoltage of 4 kV, sheath gas flow set to 50 au, auxiliary gas flow set to10 au and sweep gas flow set to 1 au. The capillary ion transfertemperature was 320° C. and the S-lens RF level was set to 50 voltage.Protein Deconvolution software (Thermo Scientific) was used todeconvolute the charge envelopes of protein species in samples.

Data was analyzed using the Thermo protein deconvolution package.Briefly the charge envelope for each observed species was quantitativelydeconvoluted to determine the mass and intensity of each parent species(modified or unmodified protein). % modification was calculated based onthe deconvoluted peak intensities.

Other in vitro analyses are as follows:

Inhibition of Cell Growth:

The ability of the subject compounds to inhibit RAS-mediated cell growthis assessed and demonstrated as follows. Cells expressing a wildtype ora mutant RAS are plated in white, clear bottom 96 well plates at adensity of 5,000 cells per well. Cells are allowed to attach for about 2hours after plating before a compound disclosed herein is added. Aftercertain hours (e.g., 24 hours, 48 hours, or 72 hours of cell growth),cell proliferation is determined by measuring total ATP content usingthe Cell Titer Glo reagent (Promega) according to manufacturer'sinstructions. Proliferation EC50s is determined by analyzing 8 pointcompound dose responses at half-log intervals decreasing from 100 M.

Inhibition of RAS-Mediated Signaling Transduction:

The ability of the compounds disclosed herein in inhibiting RAS-mediatedsignaling is assessed and demonstrated as follows. Cells expressing wildtype or a mutant RAS (such as G12C, G12V, or G12A) are treated with orwithout (control cells) a subject compound. Inhibition of RAS signalingby one or more subject compounds is demonstrated by a decrease in thesteady-state level of phosphorylated MEK, phosphorylated ERK,phosphorylated RSK, and/or Raf binding in cells treated with the one ormore of the subject compounds as compared to the control cells.

Each of the compounds in Table 1 were tested according to the abovemethods and found to covalently bind to KRAS G12C to the extent of atleast about 10% (i.e., at least about 10% of the protein present in thewell was found to be covalently bound to test compound).

TABLE 6 Activity of Representative Compounds of Structure (I)* BindingNo. Binding % No. Binding % No. Binding % No. % I-1 +++ I-2 + I-3 +++I-4 ++ I-5 + I-6 +++ I-7 ++ I-8 +++ I-9 ++ I-10 +++ I-11 +++ I-12 ++I-13 +++ I-14 +++ I-15 +++ I-16 +++ I-17 ++ I-18 +++ I-19 ++ I-20 +++I-21 + I-22 ++ I-23 ++ I-24 +++ I-25 +++ I-26 +++ I-27 +++ I-28 + I-29+++ I-30 +++ I-31 +++ I-32 + I-33 +++ I-34 +++ I-35 ++ I-36 +++ I-37 +++I-38 +++ I-39 +++ I-40 +++ I-41 +++ I-42 +++ I-43 +++ I-44 +++ I-45 +++I-46 +++ I-47 +++ I-48 +++ I-49 +++ I-50 ++ I-51 +++ I-52 + I-53 +++I-54 + I-55 +++ I-56 +++ I-57 +++ I-58 +++ I-59 +++ I-60 ++ I-61 +++I-62 +++ I-63 +++ I-64 +++ I-65 +++ I-66 +++ I-67 +++ I-68 +++ I-69 +++I-70 +++ I-71 +++ I-72 +++ I-73 +++ I-74 +++ I-75 +++ I-76 +++ I-77 +++I-78 +++ I-79 + I-80 +++ I-81 + I-82 +++ I-83 +++ I-84 +++ I-85 +++ I-86+++ I-87 +++ I-88 + I-89 +++ I-90 +++ I-91 +++ I-92 +++ I-93 +++ I-94+++ I-95 +++ I-96 + I-97 +++ I-98 + I-99 +++ I- +++ 100 I-101 +++ I- +I- +++ I- + 102 103 104 I-105 +++ I- +++ I- +++ I- +++ 106 107 108 I-109+++ I- +++ I- + I- +++ 110 111 112 I-113 +++ I- +++ I- +++ I- +++ 114115 116 I-117 + I- +++ I- + I- ++ 118 119 120 I-121 +++ I- +++ I- +++ I-+++ 122 123 124 I-125 +++ I- + I- +++ I- +++ 126 127 128 I-129 +++ I-+++ I- +++ I- +++ 130 131 132 I-133 ++ I- +++ I- +++ I- +++ 134 135 136I-137 +++ I- +++ I- +++ I- +++ 138 139 140 I-141 +++ I- +++ I- +++ I-+++ 142 143 144 I-145 +++ I- +++ I- ++ I- +++ 146 147 148 I-149 +++ I-+++ I- +++ I- +++ 150 151 152 I-153 +++ I- +++ I- +++ I- +++ 154 155 156I-157 +++ I- +++ I- +++ I- +++ 158 159 160 I-161 +++ I- + I- +++ I- ++162 163 164 I-165 ++ I- ++ I- ++ I- +++ 166 167 168 I-169 ++ I- ++ I- ++I- +++ 170 171 172 I-173 + I- + I- ++ I- ++ 174 175 176 I-177 +++ I- ++I- + I- +++ 178 179 180 I-181 + I- + I- +++ I- + 182 183 184 I-185 + I-++ I- + I- ++ 186 187 188 I-189 ++ I- + I- +++ I- +++ 190 191 192 I-193+++ I- + I- ++ I- ++ 194 195 196 I-197 ++ I- ++ I- +++ I- ++ 198 199 200I-201 ++ I- ++ I- ++ I- ++ 202 203 204 I-205 ++ I- +++ I- ++ I- ++ 206207 208 I-209 ++ I- +++ −−− −−− −−− −−− 210 + indicates binding activityup to 50% ++ indicates binding activity from 50 to 90% +++ indicatesbinding activity greater than 90%

TABLE 7 Activity of Representative Compounds of Structure (II) BindingBinding No. Binding % No. % No. Binding % No. % II-1 + II-2 +++ II-3 +++II-4 + II-5 + II-6 ++ II-7 + II-8 + II-9 + II-10 +++ II-11 + II-12 +II-13 ++ II-14 −−−− II-15 −−−−− −−−−− −−−−− + indicates binding activityup to to 50% ++ indicates binding activity greater than 50% and lessthan 75% +++ indicates binding activity of 75% or greater +++ indicatesbinding activity of 90% or greater

TABLE 8 Activity of Representative Compounds of Structure (III) BindingNo. Binding % No. Binding % No. Binding % No. % III-1 ++ III-2 + III-3++ III-4 + III-5 ++ III-6 +++ III-7 + III-8 ++ III-9 ++ III-10 + III-11+++ III-12 + III-13 + III-14 ++ III-15 ++ III-16 + III-17 ++ III-18 +III-19 +++ III-20 ++ III-21 ++ III-22 + III-23 + III-24 +++ III-25 +++III-26 ++ III-27 +++ III-28 +++ III-29 + III-30 +++ III-31 + III-32 ++III-33 + III-34 + III-35 +++ III-36 +++ III-37 ++ III-38 ++ III-39 +III-40 ++ III-41 ++ III-42 ++ III-43 ++ III-44 +++ + indicates bindingactivity up to 50% ++ indicates activity from 50% to 90% +++ indicatesbinding activity greater than 90%

Example 29 Whole Blood Stability of Compounds of Structure (III)

Representative compounds of structure (III) were tested for their wholeblood stability as follows:

Test compounds were prepared as a 500 μM stock solution in DMSO (Adding10 μl of 10 mM DMSO stock solution to 190 μl of 100% DMSO). Whole bloodwas thawed on ice. A whole blood plate was prepared by adding 460 μl ofthe whole blood (different species as needed) to a 96-well in ml deepwell plate. The whole blood plate was preincubated at 37° C. for 10 min.4 μl of compound solution and 396 μl of whole blood was added to theplate and mixed thoroughly. Each sample was aliquoted (30 μl) to theincubation plate (cluster tubes) and quenched at time zero with ice-cold100% ACN, and the incubation plates were added to the 37° C. incubator(200 μl).

The time zero sample was maintained at 4° C. until centrifuged. Allother samples were quench at different time points (1, 2, 4 hr),vortexed for 30 seconds and centrifuged at 3500 rpm for 15 min at 4° C.30 μl of supernatant was added to 170 μl 0.1% FA aqueous solution andthe sample was analyzes by LC/MS/MS.

For comparative purposes, the following compound (A) was also tested:

Table 3 provides whole blood stability for the representative compoundsand the comparative compound. The data show that compounds of structureIII, wherein at least one of R^(3a), R^(3b), R^(4a) and R^(4b) is not H,have a better whole blood stability than compound A, wherein each ofR^(3a), R^(3b), R^(4a) and R^(4b) are H.

TABLE 9 Whole Blood Stability of Representative Compounds and aComparative Compound Whole Blood Stability Compound (T_(1/2)) hr. MouseA 3.99 III-14 6.2 III-15 11.1 III-17 12.5 III-18 8.8 III-20 10.6III-21 >12.0 III-22 >12.0 III-23 >12.0 III-24 10.4 III-29 10.9 III-379.9

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification or theattached Application Data Sheet are incorporated herein by reference, intheir entirety to the extent not inconsistent with the presentdescription.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1-102. (canceled)
 103. A compound having the following structure (I):

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof,wherein: A is N; G¹ and G² are each independently N or CH; L¹ is a bondor NR⁷; L² is a bond or alkylene; R¹ is heteroaryl; R^(2a), R^(2b) andR^(2c) are each independently H, amino, halo, hydroxyl, C₁-C₆ alkyl,C₁-C₆ alkylaminyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl,heteroaryl or aryl; R^(3a), R^(3b), R^(4a) and R^(4b) are, at eachoccurrence, independently H, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆ alkyl,C₂-C₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; R^(5a) and R^(5b) are, at each occurrence, independentlyH, hydroxyl, halo or C₁-C₆ alkyl, or R^(5a) and R^(5b) join to form oxo;R⁶ is heterocyclyl; R⁷ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl orheterocyclylalkyl; m¹ and m² are each independently 1, 2 or 3; n is 0; Xis a bond; and E is an electrophilic moiety capable of forming acovalent bond with the cysteine residue at position 12 of a KRAS, HRASor NRAS G12C mutant protein, wherein each occurrence of alkyl, alkylene,aryl, heteroaryl, heterocyclyl, alkynyl, hydroxylalkly, alkoxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy,cycloalkyl and heterocyclylalkyl is optionally substituted with one ormore substituents unless otherwise specified, the optional substituentsbeing selected from the group consisting of aminyl, cyano, hydroxyl,imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C₁-C₁₂alkyl, C₁-C₆ alkylaminylcarbonyl, aminylcarbonylC₁-C₆ alkyl, C₁-C₁₂haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆haloalkoxyalkyl, cyanoC₁-C₆ alkyl, C₁-C₆ alkylcycloalkyl, C₁-C₆alkylheterocycloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkylaminyl, C₁-C₆alkylcarbonylaminyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkenylcarbonylaminyl,C₁-C₆ thioalkyl, aryl, aralkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl,aminylcarbonylC₃-C₈ cycloalkyl, C₃-C₈ cycloalkylaminylcarbonyl, C₃-C₈fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and heteroarylalkyl, and wherein: i) each arylcomprises a 6- to 18-membered carbocyclic aromatic ring radical; ii)each heterocyclyl comprises a 3- to 18-membered non-aromatic ringradical having one to twelve ring carbon atoms and from one to six ringheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur; and iii) each heteroaryl comprises a 5- to 14-membered ringradical comprising hydrogen atoms, one to thirteen ring carbon atoms,one to six ring heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur, and at least one aromatic ring.
 104. Thecompound of claim 103, wherein the compound has the following structure(I′a):

wherein:

represents a double or triple bond; Q is —C(═O)—, —C(═NR^(8′))—,—NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—; R⁸ is H, C₁-C₆ alkyl,hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl,cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C₃-C₈ cycloalkyl orheterocycloalkyl; R^(8′) is H, —OH, —CN or C₁-C₆ alkyl; when

is a double bond then R⁹ and R¹⁰ are each independently H, halo, cyano,carboxyl, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, orR⁹ and R¹⁰ join to form a carbocyclic, heterocyclic or heteroaryl ring;and when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆ alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.
 105. The compound ofclaim 104, wherein the compound has one of the following structures(I′b), (I′c), (I′d) or (I′e):


106. The compound of claim 103, wherein R¹ comprises nitrogen.
 107. Thecompound of claim 106, wherein R¹ is indazolyl or quinolinyl.
 108. Thecompound of claim 103, wherein R¹ is substituted with one or moresubstituents.
 109. The compound of claim 108, wherein R¹ is substitutedwith halo, amino, hydroxyl, C₁-C₆ alkyl, cyano, C₁-C₆ haloalkyl, C₁-C₆alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl,boronic acid, —OC(═O)R, phosphate, phosphoalkoxy or C₁-C₆alkylcarbonyloxy, or combinations thereof, wherein R is C₁-C₆ alkyl.110. The compound of claim 108, wherein R¹ is substituted with hydroxylor C₁-C₆ alkyl, or both.
 111. The compound of claim 103, wherein R¹ hasone of the following structures:


112. The compound of claim 103, wherein R^(2c) is H.
 113. The compoundof claim 103, wherein R^(2a) and R^(2b) are each halo.
 114. The compoundof claim 103, wherein R^(2a) is fluoro.
 115. The compound of claim 103,wherein R^(2b) is chloro.
 116. The compound of claim 103, wherein R⁶ isazetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
 117. The compoundof claim 116, wherein R⁶ is substituted.
 118. The compound of claim 117,wherein R⁶ is substituted with C₁-C₆ alkyl, C₁-C₆ alkylaminyl,heterocyclyl or spiro-heterocyclyl, or combinations thereof.
 119. Thecompound of claim 103, wherein R⁶ has one of the following structures:


120. The compound of claim 104, wherein Q is —C(═O)—.
 121. The compoundof claim 104, wherein each of R⁹ and R¹⁰ are H.
 122. The compound ofclaim 103, wherein E has one of the following structures:


123. The compound of claim 103, wherein L¹ is a bond.
 124. The compoundof claim 103, wherein L² is a bond.
 125. The compound of claim 103,wherein R^(3a), R^(3b), R^(4a) and R^(4b) are, at each occurrence,independently H or C₁-C₆ alkyl.
 126. The compound of claim 103, whereinthe compound has one of the following structures:


127. A substantially purified atropisomer of the compounediated of claim103.
 128. A pharmaceutical composition comprising a compound of claim103 and a pharmaceutically acceptable carrier.
 129. A method fortreatment of cancer, the method comprising administering an effectiveamount of the pharmaceutical composition of claim 128 to a subject inneed thereof.
 130. The method of claim 129, wherein the cancer ismediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.
 131. Themethod of claim 129, wherein the cancer is a hematological cancer,pancreatic cancer, MYH associated polyposis, colorectal cancer or lungcancer.